bluuebunny/crossref_metadata_2025 huggingface dataset:
Delays from neoadjuvant chemotherapy to interval debulking surgery and survival in ovarian cancer.
Authors: Liu Ying L , Zhou Qin , Iasonos Alexia , Filippova Olga T. , Chi Dennis , Zivanovic Oliver , Sonoda Yukio , Gardner Ginger J. , Broach Vance , O'Cearbhaill Roisin Eilish , Konner Jason A. , Aghajanian Carol , Long-Roche Kara C. , Tew William P.
Published: May 2019

5552

Background: Prolonged time from primary surgery to chemotherapy is associated with worse survival in ovarian cancer (OC); however, the impact of prolonged time from neoadjuvant chemotherapy (NACT) to interval debulking surgery (IDS) is unknown. Given increasing utilization of NACT, we seek to evaluate the role of delays from NACT to IDS (TIDS) on survival. Methods: At a single center, we prospectively identified 224 women with newly diagnosed stage III/IV OC given NACT from 7/1/15 to 12/1/17. Clinical characteristics were abstracted by two independent reviewers. Delays in TIDS were defined as time from last preoperative carboplatin to IDS > 6 weeks. Fisher’s exact/Wilcoxon rank sum tests were used to compare clinical characteristics by delay in TIDS. Kaplan Meier method was used to estimate progression-free (PFS) and overall survival (OS) from date of IDS. Log-rank test/multivariate CoxPH models were used to examine differences by delay groups, adjusting for covariates. Results: Of the 224 women, 159 underwent IDS, and 34 (21%) experienced TIDS delays. These women were older (median 68 vs. 65 years, p = 0.05) and had more preoperative NACT cycles (median 6 vs. 4, p = 0.003). Patients with delays in TIDS also had a longer interval from pathological diagnosis to start of NACT (TNACT), median 22 vs. 17 days, p = 0.01, and interval from IDS to postoperative chemotherapy (TPOC), median 37 vs. 30 days, p = 0.01; however, neither TNACT nor TPOC predicted survival, p > 0.05. On univariate analysis, delays in TIDS were significantly associated with worse OS (HR 2.4 95% CI 1.2-4.8, p = 0.01); however, this was attenuated in multivariate models (HR 1.66 95% CI 0.8-3.4, p = 0.17), adjusting for age, stage and complete gross resection (CGR). On univariate analysis, delays in TIDS were not associated with PFS (HR 1.55 95% CI 0.97-2.5, p = 0.062), and in multivariate models, increase in number of preoperative NACT cycles (p = 0.005) and lack of CGR (p < 0.001) were the only variables predictive of worse PFS. Conclusions: Delays in TIDS are associated with OS, but not after adjustment for age, stage and CGR, suggesting a need to maximize cytoreduction regardless of delays in NACT. The role of preoperative NACT cycles on survival should be further studied.
Comprehensive genomic analysis of mucinous ovarian cancer reveals unique therapeutic vulnerabilities.
Authors: Cheasley Dane Anthony
Published: May 2019

5571

Background: Mucinous ovarian carcinoma (MOC) is a rare subtype of epithelial ovarian cancer that responds poorly to ovarian chemotherapies and has an unknown etiology. It is diagnostically challenging and can be confused with metastases from gastro-intestinal tract primaries. The GAMuT study is a multi-national effort to understand molecular drivers and cell of origin of this rare tumour, including identification of a genetic progression model and novel therapeutic options. Methods: We performed RNAseq (n = 67), exome sequencing (n = 61), SNP arrays (n = 67) and whole genome sequencing (n = 5) on MOC and precursor lesions. A subset of ~500 genes was further evaluated by targeted sequencing, including 129 MOC, 23 borderline mucinous tumours (non-invasive) and 23 extra-ovarian mucinous metastases. Immunohistochemistry data was collected for CK7, CK20, ER, PAX8, p53 and HER2 (n = 162-256). Extensive pathology review was performed and associated clinical data obtained. Results: Comparison with TCGA and other data sets showed that MOC are distinct from mucinous tumours from other organs, including colorectal, appendiceal and gastric cancers. Our data supports a clear genetic progression model from benign and borderline precursors to both low- and high-grade MOC. TP53 mutation, ERBB2 amplification and increasing copy number changes were key events associated with progression to invasive disease, including a novel amplicon on 9p13. Copy number aberration burden was significantly associated with poor survival. We identified several recurrent mutational events suggesting utility of an existing targeted therapy, including ERBB2 amplification (26%), ERBB3 mutation (4%) and BRAF mutation (9%). MOC could be included in clinical trials for novel agents targeting TP53 missense mutation (46%), RNF43 mutation (12%), PIK3CA mutation (8%) and KRAS/ NRAS mutations (66%). Other frequent events included CDKN2A inactivation (57%), ARID1A mutation (9%) and TP53 inactivating mutations (15%). Conclusions: MOC of any grade can derive from a primary ovarian tumour precursor, and is distinct from extra-ovarian metastases. MOC is genetically diverse and advanced disease should be assessed for targetable mutations which may provide novel therapeutic options.
BRCA tumor test in ovarian cancers: The changing role of molecular pathology in the era of PARP inhibitor (PARPi) therapy.
Authors: Fumagalli Caterina , Guerini Rocco Elena , Tomao Federica , Betella Ilaria , Rappa Alessandra , Viale Giuseppe , Peccatori Fedro , Colombo Nicoletta , Barberis Massimo
Published: May 2019

5572

Background: The PARPi Olaparib has been approved in maintenance setting of recurrent platinum-sensitive and BRCA mutated, ovarian cancer (OC) patients. However, according to the striking results of SOLO 1 trial, it could be shortly proposed even to newly diagnosed BRCA mutated OC women. We report the results of the implementation of tumor BRCA test in diagnostic setting within the frame of institutional workflow for the management of OC patients. Methods: 223 women with OC were consecutively referred over 25 months to tumor BRCA test. The test was requested by gynecologic oncologist at the diagnosis of non-mucinous and non-borderline OC, upon discussion on the implications of the test result and written consent collected for each patient. Formalin-fixed paraffin embedded (FFPE) specimens of OC were tested using the automatized “Oncomine BRCA Research Assay” Next Generation Sequencing (NGS) panel. The tumor BRCA test was also performed on 5 archetypal cytological samples from ascites. Results: All the cases were considered adequate for the NGS analysis according to the tumor cell content (more than 10%) and the DNA yield extracted (more than 10 ng). The tumor BRCA test had a successful rate of 99.1% . The median Turn-Around Time (TAT) was 17 calendar days, from 33 days of the first trimester to 14 days of the last trimester of this analysis. Overall BRCA1 or BRCA2 pathogenic (P)/likely pathogenic (LP) mutations were found in 62 (28.1%) cases and variants of uncertain significance (VUS) in 25 (11.3%) cases, including 3 cases with a BRCA1 P variant and a concurrent BRCA2 VUS alteration. In detail, 47 P/LP variants and 16 VUS were identified in BRCA1 whereas 15 P/LP mutations and 9 VUS occurred in BRCA2. Complete concordance in tumor BRCA test results were seen between ascites cytological samples and matched tumors. Conclusions: The tumor BRCA test could be implemented in routine diagnostic setting, at diagnosis of non-mucinous and non-borderline OC. The test could be performed on FFPE specimens, had an high successful rate and a TAT compatible with clinical needs. The promising data on cytological samples will be confirmed in larger series.
Real-world bevacizumab utilization and outcomes in first-line ovarian cancer.
Authors: Monberg Matthew J. , Hall Jennifer P , Moon Rebecca , Higson Olivia , McLaurin Kimmie , Dalvi Tapashi
Published: May 2019

5578

Background: Bevacizumab (B) is approved in combination with carboplatin and paclitaxel, followed by B monotherapy, for the treatment of advanced ovarian cancer (OC) following surgery. We sought to describe B utilization and outcomes of B in first-line (1L) OC within the US and EU. Methods: This cross-sectional study included patients who were actively receiving treatment for OC. Data were collected at a single time point from 2496 patient forms between December 2017 and March 2018 from 340 oncologists/ gynecologists across the US, France, Germany, Italy, Spain, and the UK. Patients were platinum sensitive if progression was noted > 6 months after frontline platinum therapy and resistant if the interval was 0-6 months. This analysis included patients who received 1L chemotherapy (chemo) with no maintenance or 1L chemo with bevacizumab maintenance. Results: B was used in combination with chemo at 1L and as 1L maintenance monotherapy in 11% total study patients. Those receiving 1L + B were more likely to have Stage IV disease, have good performance status (PS) at diagnosis, and receive BRCA testing than patients receiving chemo only. Treatment response, platinum sensitivity, and activities of daily living are shown in the Table. Results did not vary by BRCA status. Conclusions: This study highlights differences in patient characteristics and outcomes between patients receiving/ who received 1L chemo only and those receiving/ who received B, however, this study was not designed to formally compare 1L treatment options. [Table: see text]
Lynch-like syndrome in endometrial cancer: Features of a growing population.
Authors: Gordhandas Sushmita , Kahn Ryan , Maddy Brandon Paul , Baltich Nelson Becky , Askin Gulce , Christos Paul J. , Holcomb Kevin , Caputo Thomas A. , Chapman-Davis Eloise , Frey Melissa Kristen
Published: May 2019

5585

Background: Current guidelines recommend screening all endometrial cancers (EC) and colorectal cancers (CRC) for defects in DNA mismatch repair (MMR). Tumor screening combined with germline genetic testing can categorize patients into three groups: intact-MMR, Lynch syndrome (LS), and Lynch-like syndrome (LLS). Our objective was to describe features of the growing population of patients with LLS in EC and compare to existing CRC literature. Methods: A systematic search of databases between 1990-2018 identified studies of EC patients with tumor testing (MMR immunohistochemistry or microsatellite instability) and germline assessment for LS. Data on clinicopathologic features was abstracted when available. Associations between LS, LLS, and intact-MMR were analyzed using descriptive statistics. Results: The comprehensive search produced 3,427 publications; 29 met inclusion criteria. Abstracted data and features of each group are presented in the table. Conclusions: In EC, LLS closely resembles LS with younger age at diagnosis, more advanced stage and higher grade as compared to patients with intact-MMR. LLS in EC is similar to intact-MMR in regard to histology, and family history of LS-associated cancer. The CRC literature is limited, but reports LS and LLS have similar stage, grade and histology. In CRC, LS and LLS are diagnosed at a younger age, and are more likely to have family history of LS-associated cancers than intact-MMR. Features of EC with intact-MMR, LLS, and LS. [Table: see text]
Genomic biomarkers of recurrence in low-grade, early-stage endometrial adenocarcinoma.
Authors: Hwang Katie Lee , Hwang William L. , Howitt Brooke E. , King Martin T. , Stover Elizabeth , Matulonis Ursula A. , Lee Larissa Janeen
Published: May 2019

5588

Background: Endometrial cancer is the most common gynecologic malignancy in developed countries with over 60,000 new cases diagnosed in the United States each year. Adjuvant therapy is often omitted for low-risk, early-stage disease (FIGO stage IA, grade 1) but 1 in 20 women suffer recurrence after surgery alone. Hence, there is an important need for biomarkers of recurrence in this population to guide therapeutic management. Methods: We retrospectively analyzed 74 patients with FIGO stage 1A, grade 1 endometrial endometrioid adenocarcinoma treated at our institution with hysterectomy alone between 2009-2016. All patients had targeted genomic assessment of their tumors (OncoPanel; somatic mutations, copy number variations and structural variants across 300 cancer genes). The primary outcome of interest was freedom from recurrence (FFR). Outcomes were compared by the logrank test and survival estimates calculated by Kaplan-Meier method. Results: We identified 14 patients who recurred at a median time of 23.6 months after surgery and 60 patients without recurrence at a median follow-up of 38.9 months. Age (median 57 years; log-rank p = 0.91) and BMI (median 31 kg/m2; log-rank p = 0.21) were not associated with risk of recurrence. The median somatic mutation count in the cohort was 8. Patients with more than 8 somatic mutations had a significantly higher risk of recurrence (3-year FFR: 74% vs 90%; log-rank p = 0.004). At the level of individual genes, there were four genes that were significantly associated with recurrence: CTNNB1 (p = 0.046), RHPN2 (p = 0.020), SF1 (p = 0.044), SQSTM1 (p = 0.034). Patients with a mutation in one or more of these four genes had a significantly higher risk of recurrence (3-year FFR: 62% vs 93%; log-rank p = 0.0004). Conclusions: We have identified overall somatic mutation burden and mutations in a subset of four genes ( CTNNB1, RHPN2, SF1, SQSTM1) as determined by a validated 300-gene panel used in routine clinical practice as prognostic biomarkers for patients with low-risk, early-stage endometrial endometrioid adenocarcinoma. These patients may benefit from the addition of adjuvant therapy. Validation with larger cohorts and prospective studies is warranted.
Breast cancer treatment according to pathogenic variants in cancer susceptibility genes in a population-based cohort.
Authors: Kurian Allison W. , Ward Kevin C. , Abrahamse Paul , Hamilton Ann S , Deapen Dennis , Morrow Monica , Katz Steven J.
Published: May 2019

560

Background: Increasing use of germline genetic testing may have unintended consequences on breast cancer treatment. We do not know whether treatment deviates from guidelines for women with pathogenic variants (PV) in cancer susceptibility genes. Methods: SEER data for all women aged ≥20 years, diagnosed with breast cancer in 2014-15 and reported to Georgia and California registries (N = 77,588) by December 1, 2016 were linked to germline genetic testing results from 4 laboratories that did nearly all clinical testing. We examined first course of therapy (before recurrence or progression) of stage < IV patients who linked to a genetic test: bilateral mastectomy (BLM) in candidates for surgery (unilateral, stages 0-III); post-lumpectomy radiation in those with an indication (all but age ≥70, stage I, hormone receptor (HR)-positive and HER2-negative); and chemotherapy in those without a definitive indication (stage I-II, HR-positive, HER2-negative and 21-gene recurrence score < 30). We report the percent treated based on multivariable modeling, adjusted for age, race, stage, grade, insurance and socioeconomic status. Results: The table shows that 9% of patients who linked to a genetic test result had a PV (N = 1,283). Compared to women with negative results,women with BRCA1/2 PVs were more likely to receive BLM, more likely to receive chemotherapy without definitive indication, and less likely to receive indicated radiation in their first course of therapy. Lower-magnitude effects were seen with other PVs but not variants of uncertain significance (VUS). Conclusions: In a population-based setting, women with PVs in BRCA1/2 or other cancer susceptibility genes may have a higher risk of receiving locoregional and systemic treatment that does not follow guidelines. [Table: see text]
No relationship of axillary total tumor load (TTL) by PCR (OSNA) in early breast cancer and local and distant clinical outcomes.
Authors: Ales-Martinez Jose , Tur Raquel , Parra Juan , Ceballos Jaime , Filipovich Elena , Segovia Beatriz , Revestido Rafael , De Castro ANA , Blanco Paz , Velasco María José , Martin Maria Rocio
Published: May 2019

564

Background: The study of sentinel lymph nodes (SLN) assessed by One Step Nucleic Acid Amplification (OSNA, Sysmex, Kobe, Japan) creates a new variable, Total Tumor Load (TTL). This variable is defined as the total number of CK19 mRNA copies in all positive SLN (copies/microL). The latest edition of the Spanish Oncological Gynecology Society (SEGO) Guideline (2017) proposes a complete axillary lymph node dissection (ALND) when TTL is 15,000 copies or more in early breast cancer. In our center we are using OSNA to ascertain if there is axillary node involvement but the decision to proceed to ALND is based on Z0011 criteria. We want to determine if there is a correlation between clinical outcomes and TTL values, between TTL and pathological variables and if TTL is a useful tool to decide when to complete an ALND. Methods: Clinicopathological and follow up data were obtained from all patients with invasive breast cancer and SLN assessed by OSNA between 2011 and 2017 at our center. Results: A total of 321 patients underwent SNB assessed by OSNA with an average follow-up of 56 months. 320 were female and 1 male. Age range 27-89 years (mean 58.9). 85 % were ductal, 10 % lobular and 5 % other. 53.5% were luminal A, 28.66% luminal B, 7.78%, triple negative, 4.3%, Her2 positive and 4.3%. luminal B-Her2 positive.TTL was equal to 0 in 183 cases and greater than zero in 138 cases.71 cases showed a TTL higher than 15,000 copies. Only 21 cases met Z0011 criteria and had ALND. As of now, 3 patients have had locoregional relapse and 8 metastatic disease. 12 have died, only two from metastatic breast cancer. Conclusions: Using Z0011 criteria, we have adequate clinical outcomes with a low rate of ALND; If we had based the axillary management on TTL values we would have multiplied the number of ALND by a factor of 3.3 (from 21 to 71); We have observed a tendency to higher TTL in luminal phenotypes and to lower TTL in HER2 positive and triple negative subtypes; Work is in progress to increase our sample size.
Gene expression comparison between primary triple-negative breast cancer and matched axillary lymph node metastasis.
Authors: Srour Marissa K. , Gao Bowen , Dadmanesh Farnaz , Qu Ying , Cui Xiaojiang , Giuliano Armando E.
Published: May 2019

565

Background: Sentinel lymph node (SLN) biopsy guides breast cancer treatment and prognostication. To date, there have been few studies examining the genetics of SLN metastasis in triple negative breast cancer (TNBC). The aim of this study is to characterize and compare gene expression patterns of primary breast cancers and autologous matched SLN metastases. Methods: Patients with stage 2-3 ER/PR negative, HER2 negative TNBC with macrometastasis to the SLN who did not have neoadjuvant therapy were selected. The tumor-specific area was isolated from breast and SLN paraffin embedded tissue sections. Gene expression of a panel of 2567 cancer-associated genes was analyzed with the HTG EdgeSeq system coupled with the Illumina Next Generation Sequencing (NGS) platform. Results were validated with RNA-scope assays for RNA in situ detection. Results: 18 pairs of TNBC and matched SLN metastasis were analyzed for 2567 genes. Compared with the primary TNBC, SLN metastasis had 34 statistically significant upregulated genes and 31 downregulated genes. SLN metastasis had at least a 5-fold change (FC) in upregulation in 3 genes and downregulation in 3 genes, compared to primary TNBC [Table]. Notably, there was an upregulation of anti-apoptosis and survival signaling genes (i.e. BIRC3) in the SLN metastasis. There was also an upregulation of chemotaxis genes (CCL13, CXCL19, CXCL21, CXCR5, TNFSF11, p<0.001). The most striking feature is the downregulation of genes known to regulate cell microenvironment interaction (MMP2, MMP14, COL1A1, COL1A2, COL5A2, COL6A6, COL11A1, COL17A1). Conclusions: In TNBC, SLN metastasis has a distinct gene expression profile. Genes associated with anti-apoptosis, survival responses, and chemotaxis are upregulated, and genes associated with regulation of extracellular matrix are downregulated. Upregulated and downregulated genes with at least a 5-fold change in gene expression in lymph node metastasis compared with TNBC.[Table: see text]
Risk stratification in earl- stage luminal breast cancer patients treated with and without RT.
Authors: Wadsten Charlotta , Whitworth Pat W. , Patel Rakesh , Savala Jess , Warnberg Fredrik , Bremer Troy
Published: May 2019

568

Background: The goal was to develop and validate a biologic signature for 10-year ipsilateral invasive breast event (IBE) risk in luminal Stage 1 breast cancer (BC) patients treated surgically and either with or without radiation therapy (RT). Methods: This cohort was from Uppsala University and Västerås Hospitals diagnosed with Stage 1 BC and treated surgically between 1987 and 2004. Treatment was neither randomized nor strictly rules based, including adjuvant RT, Hormone Therapy (HT), and Chemotherapy (CT). Biomarkers (HER2, PR, Ki67, COX2, p16/INK4A, FOXA1 and SIAH2) were assessed on tissue microarrays in PreludeDx’s CLIA lab by board-certified pathologists. Risk groups were calculated using biomarkers and clinical factors age and size. A multivariate Cox proportional hazards analysis was used to determine hazard ratio for biologic signature. 10-year IBE risk was assessed using Kaplan-Meier survival analysis. Results: There were 423 luminal cases with biomarker data having 54 IBEs, and a median follow-up of 11.8 years. There were 372 patients treated with BCS and 51 with Mastectomy, and 325 received RT, 169 received HT, and 47 received CT. In a multivariate analysis, the biologic signature (HR = 1.6, p = 0.019) and RT (HR = 0.51, p = 0.027) were associated with IBE risk adjusting for other treatments (HT and CT) and Luminal A status (p = 0.37). For patients over 50 yrs of age with luminal A disease and treated without CT (n = 205), an elevated biologic signature identified a subset of patients with a 15% (+/- 14%) 10-year IBE risk without RT (n = 38) compared to a 4% (+/-6%) IBE risk with RT (n = 72), while patients with a low biologic signature had a 10-year IBE risk of 4% (+/- 4%) without RT (n = 26) and 3% (+/-5%) IBE risk with RT (n = 69). Conclusions: With further prospective validation, the biologic signature identified herein may provide a tool enabling improved management for women diagnosed with early luminal BC.
Beyond TILs: Predictors of pathologic complete response (pCR) in triple-negative breast cancer (TNBC) patients with moderate tumor-infiltrating lymphocytes (TIL) receiving neoadjuvant therapy.
Authors: Abuhadra Nour , Hess Kenneth R. , Litton Jennifer Keating , Rauch Gaiane M , Thompson Alastair Mark , Lim Bora , Adrada Beatriz E , Mittendorf Elizabeth A. , Damodaran Senthil , Candelaria Rosalind P , Arun Banu , Yang Wei Tse , Ueno Naoto T. , Santiago Lumarie , Murthy Rashmi Krishna , Ibrahim Nuhad K. , Sahin Aysegul A. , Symmans William Fraser , Moulder Stacy L. , Huo Lei
Published: May 2019

572

Background: Increased TIL in TNBC is associated with higher rates of pCR. High TIL is also associated with improved disease free survival and overall survival. The aim of this study is to identify data cut-points of pre-treatment low, moderate and high TIL count based on pCR and to identify clinical and pathological predictors of pCR in patients with moderate TIL. Methods: We evaluated the relationship between pCR and TIL in 180 patients with stage I-III TNBC enrolled in the ARTEMIS trial (NCT02276443). Recursive portioning was used to identify cut-points. Clinical and pathological variables such as age at diagnosis, stage, race, histology as well as Ki-67, vimentin, and androgen receptor (AR) by immunohistochemistry, were evaluated in pts with moderate TIL. A multivariable logistic regression model identified variables independently, significantly associated with pCR. Results: Four TIL groups were identified with pCR rates of 23%, 31%, 48% and 78% respectively (p < 0.0001) (Table A). In the two combined moderate TIL groups, 90 (97%) pts were evaluable for the multivariate model. Stage I-II disease, high Ki-67 and low AR were associated with increased probability of pCR (Table B). The multivariable logistic regression model area under the ROC curve was 0.78 (95% CI=0.68-0.88; p<0.0001). A model of computed risk score [ Stage I-II (score 2)+Ki-67≥ 50% (score 1)+AR<10% (score 1)] predicted a probability of 67% for pCR when all three variables were favorable (Table). Conclusions: Four TIL groups were identified. In pts with moderate TIL levels, early stage disease, high Ki-67 and low AR were associated with increased probability of pCR with neoadjuvant therapy. [Table: see text]
Prognostic value of PAM50 in residual breast cancer following neoadjuvant endocrine therapy (NET): A retrospective analysis with long follow-up.
Authors: Gil Gil Miguel J. , Perez Francisco Javier , Soler Monso Teresa , Pascual Tomas , Galván Patricia , Pare Laia , Petit Anna , Falo Catalina , Stradella Agostina , Pla María Jesús , Salazar Ramon , Prat Aleix
Published: May 2019

575

Background: NET is gaining more acceptances for the management of hormonal receptors (HR)-positive breast cancer (BC). To date, the decrease of Ki-67 and PEPI score are the only prognostic factors associated with relapse-free survival after NET. PAM50 is a validated prognostic test in newly diagnosed BC; however, its value in residual tumors after NET is currently unknown. Methods: We took tumor tissues from patients of a retrospective study of 119 postmenopausal women with HR-positive stage II-III BC. Patients were diagnosed from 1997 to 2009 and were treated with NET for a median duration of 8.5 months . Median age was 74 (63-88). After NET all patients underwent surgery (73% conservative). Adjuvant treatment were endocrine therapy in 100%, radiotherapy in 76.5% and chemotherapy 7%. Median follow-up from surgery was 112 months. Median follow-up from surgery was 112 months. We observed 26 (24%) of distant relapses and 75 deaths (44 without cancer). Median overall survival was 134.8 months. RNA was extracted from FFPE tumor tissues of surgical specimens. A panel of 55 BC-related genes, including the research-based PAM50 assay (subtypes, ROR-S and ROR-P pre-defined cutpoints), androgen receptor (AR), immune genes (CD8A, CD4, PDL1 and PD1). Uni- and multi-variable Cox models were used to evaluate the association of each variable with distance recurrence free interval (DRFI). Results: PAM50 subtype distribution: Luminal A 54.3%, Normal-like 24.3%; HER2-enriched 16,5%, Luminal B 1% and basal 1%. Distribution of ROR-S groups was Low 64%, medium 30%and high 6%. Distribution of PEPI score was: 0 in 43%, 3 in 37% and 6 in 20%. Among the different variables explored, PEPI score 0 (HR 0.27 [95%IC 0.09-0.79] p=0.001), low ROR-S (HR 0.39 [95%CI 0.17-0.91] p=0.001) and high AR expression (HR 0.71 [95CI 0.53-0.96] p=0.007) were significantly associated with lower DRFI in univariate analyses. After adjusting for PEPI (with or without Normal-like tumors), ROR-S and AR remained significantly associated with outcome. Conclusions: PAM50 ROR-S and AR expression in residual tumors after NET provide independent prognostic information beyond PEPI. With further validation, these biomarkers could help clinicians in the decision-making of adjuvant chemotherapy.
Heterogeneity in signaling pathway activity within primary breast cancer and between primary and metastases.
Authors: Verhaegh Wim , van Brussel Anne , Moelans Cathy , Alves de Inda Marcia , Gil Julie , Bikker Jan Willem , den Biezen-Timmermans Eveline , Van De Stolpe Anja , van Diest Paul J.
Published: May 2019

589

Background: Treatment with targeted drugs aims to block tumor driving signaling pathway(s). Drug choice is often based on a single preoperative primary breast cancer biopsy. It is important that biopsied cancer tissue is representative for the primary tumor (PT) or metastases to treat. Little is known about pathway heterogeneity within the PT, and between PT and metastatic tumors. A novel analysis method was developed to identify and quantify activity of signal transduction pathways in cancer tissue, based on Bayesian models that infer a pathway activity score from transcription factor target gene mRNA levels (Cancer Res 2014;74:2936-45). Methods: Pathway analysis, originally developed for AffymetrixU133Plus2.0, was adapted to RT-qPCR for use on formalin fixed paraffin embedded tissue. Estrogen (ER) and androgen (AR) receptor, PI3K, Hedgehog (HH), TGFβ and Wnt pathway activities were analyzed. Samples were from multiple locations (“quadrants”) in 15 luminal A, 9 luminal B, and 8 ER-negative primary breast cancers; from subdivided quadrant samples (4 “subquadrants”) of respectively 9, 4, and 4 PTs; and from 13 distant and 24 lymph node (LN) metastases of respectively 9 and 7 matched luminal PTs. Analysis of pathway activity score (PAS) variance was performed with linear mixed models with subgroup-dependent standard deviations. Results: In primary breast cancer intra-tumor PAS variance was not larger at macroscale (“quadrant”) than at microscale (“subquadrant”). For ER, AR, HH, and Wnt pathways, PAS variation was higher between distant metastases and PT than within the PT (p < 0.0002). For HH and Wnt pathways, PAS variation was higher between LN metastases than within the PT (p < 0.002). Correlation between primary and metastatic pathway activities ranged from -0.34 for ER to 0.47/0.50 for TGFβ/HH pathways. Conclusions: A single location tissue sample was representative for the whole primary tumor with respect to signaling pathway activity, suggesting one biopsy as generally sufficient for (neo)adjuvant therapy choice. Pathway activities varied between primary cancer and metastases, indicating the necessity of metastatic sample analysis (biopsies or liquid biopsy) to improve therapy choice.
Circulating tumor DNA (ctDNA) during and after neoadjuvant chemotherapy and prior to surgery is a powerful prognostic factor in triple-negative breast cancer (TNBC).
Authors: Cavallone Luca , Aguilar Adriana , Aldamry Mohammed , Lafleur Josiane , Brousse Susie , Lan Cathy , Alirezaie Najmeh , Bareke Eric , Majewski Jacek , Pelmus Manuela , Ferrario Cristiano , Marcus Elizabeth A. , Robidoux Andre , Discepola Federico , Basik Mark
Published: May 2019

594

Background: TNBC, the most aggressive form of breast cancer, is treated primarily with chemotherapy, even before surgery (neoadjuvant chemotherapy or NAC). The prognosis and need for adjuvant therapy depends greatly on the tumor response assessed by pathology (pCR). Highly sensitive and specific ctDNA assays have been shown to be of prognostic value in the metastatic settingbut not yet in earlier settings. Methods: Tissue was collected from 26 Q-CROC-03 clinical trial TNBC patients before, during and after NAC, prior to surgery. Whole exome sequencing on tumor tissues was used to select single nucleotide variants with high allele frequency (VAF), prioritizing TP53, to generateindividual digital droplet PCR (ddPCR) assays. An average of 5 variants (range 1-12) per patient were tested, for a total of 121 variants. A detection threshold was defined for each variant from a pool of normal controls. Median follow-up was 55 months. Results: ctDNA was detectable in 96% of patients at baseline, but 20% of the 121 variants were not detectable at any time point. At baseline, the mean VAF of all analyzed variants, but not of TP53 variants alone, was significantly correlated (p < 0.05) with tumor factors (tumor size, stage, grade, nodal status before and at surgery, RCB score) but not with patient age or BRCA1/2 mutation status. 87 variants (74%) were detected at baseline and their VAF fell by 86% after 1 cycle of chemotherapy (T1). The detection of ctDNA at T1 was associated with DFS (p = 0.027) while the detection of ctDNA at the last post-chemotherapy pre-surgery time point (T4) was strongly associated with pathological complete response (pCR) and both DFS (p = 0.013) and OS(p = 0.006). At this time point, 5 of 41 variants (12%) were detected in pCR patients vs 42 of 80 (53%) in non-pCR, while only 6 of the 15 (40%) non-pCR patients had detectable TP53 variants. Interestingly, for variants detected at baseline, the positive predictive value of T4 ctDNA for disease recurrence was 69%, similar to that of non-pCR, while the negative predictive value of no ctDNA at T4 was 89% for disease recurrence vs 80% for pCR. Conclusions: ctDNA detection after NAC prior to surgery is strongly predictive of disease-free survival and overall survival and is comparable to pCR as a prognostic factor in our cohort (NCT01276899).
A multicenter prospective observational study of nutritional status on survival in locally advanced nasopharynx cancer treated by induction chemotherapy and chemoradiotherapy.
Authors: Miao Jingjing , Wang Lin , Hu Chaosu , Lin Shaojun , Tan Sze Huey , Ong Enya , Chen Xiaozhong , Chen Yuan yuan , Zhong Yahua , Jin Feng , Lin Qin , Lin Shaomin , Hu Xuefeng , Zhang Ning , Wang Rensheng , Wang Cong , Shi Hanping , Chua Melvin Lee Kiang , Xie Conghua , Zhao Chong
Published: May 2019

6036

Background: We conducted a multicenter prospective study (NCT02575547) to investigate the association between longitudinal nutritional status and survival in locally advanced nasopharynx cancer (LA-NPC) treated with induction chemotherapy and concurrent chemoradiotherapy (IC-CCRT). Methods: All patients with biopsy-proven LA-NPC and planned for IC-CCRT were recruited from ten institutions. IC entailed 2 cycles of docetaxel 75mg/m2/3w and cisplatin 75mg/m2/3w; CCRT entailed 2-3 cycles cisplatin 100mg/m2/3w and IMRT (70-72Gy/30-32fr). Study parameters included weight loss (WL), % of ideal body weight (%IBW), body mass index (BMI), nutrition risk screening 2002 (NRS2002), patient-generated subjective global assessment (PG-SGA), and EORTC QLQ-C30 that were collected at the following time-points: baseline (T1), 1 w pre-2nd IC (T2), 1 w pre-CCRT (T3), 4 w mid-CCRT (T4), end-CCRT (T5), 3 mo post-CCRT (T6), 1 y post-CCRT (T7), 2 y post-CCRT (T8). Results: 186 patients were recruited; 171 were eligible for analysis. Median follow-up was 35.8 mo (range 12.3-46.1 mo). Compliance rates were 97.7% (167/171) and 87.7% (150/171) for IC and CCRT, respectively; all except one completed RT. Longitudinal assessment indicated the worst nutritional status at T5, followed by recovery at T8: 27.1% with %IBW <90%; 69.2% with WL ≥5%, which was also associated with a worsened QOL (OR = 6.23 for QOL change ≥25.0, P = 0.012). Interestingly, T1 nutritional status was not associated with prognosis (P >0.05 for all). However, nutritional parameters at T5 were significantly associated with survival; %IBW <90% was the strongest predictor for inferior DMFS (HR = 2.669) and OS (HR = 4.661) among all parameters (multivariable-adjusted P <0.05). Subgroup analyses revealed that %IBW <90%, WL ≥10% at T5 represented the most adverse subset of patients (Table). Conclusions: Here, we show that poor nutrition despite systemic intensification leads to inferior QOL and disease control in LA-NPC patients. This is counter-intuitive and highlights the crucial importance of paracrine factors in optimising treatment efficacy. Clinical trial information: NCT02575547. [Table: see text]
High-dose, short-duration, intra-arterial cisplatin therapy for oral cancer.
Authors: Ohmae Masatoshi , Kato Itsuro , Fujita Yusei , Meshii Noritoshi , Motoki Ayako , Nakazawa Mitsuhiro , Uzawa Narikazu
Published: May 2019

6038

Background: We developed a superselective intra-arterial chemotherapy (iaCT) approach for oral cancer wherein an intra-arterial catheter is retrogradely inserted via the superficial temporal artery (STA) and/or occipital artery (OA). In most iaCT cases, high-dose anticancer agents are administrated via the intra-arterial catheter weekly or biweekly with daily irradiation. This approach remarkably improves curative efficiency, but some adverse events, e.g., severe mucositis, dysphagia, dysgeusia, dry mouth, and radiation osteonecrosis, mainly because of irradiation, decrease the quality of life. Methods: Thirty-two patients with stage II, III, or IV oral squamous cell carcinoma were treated using this new iaCT approach. The catheter was superselectively placed in the tumor-feeding arteries by cut-down of STA or OA. The catheter was completely placed under the skin and was connected to an infusion reservoir that was subcutaneously implanted around the mastoid process via the subcutaneous tunnel, ensuring little possibility of catheter-related issues such as infection and displacement of catheter. Anticancer agents (30 mg/m2of cisplatin with/without 10 mg/m2of docetaxel) were intra-arterially administered via the reservoir twice a week for 3 weeks, 180 mg/m2/6 times in total, without irradiation. The treatment effect was assessed using computed tomography, positron emission tomography, and biopsy. Results: The response rate of this approach was 100%, with 31 and 1 case having complete response (CR) and partial response (PR), respectively. Five patients with delayed regional lymph node metastasis or PR underwent salvage surgery; 28 patients (87.5%) had disease-free survival, while 2 (6.2%) died due to local recurrence and 2 due to distant metastasis. All patients developed CTCAE v4.0 Grade 2 oral mucositis in the flow area of the intended artery, most of which disappeared in half a year. No dry mouth, dysgeusia, and eating disorder were observed because the patients did not receive radiotherapy. No systemic adverse events such as hematologic toxicity and renal and/or hepatic injuries occurred. Conclusions: This method improved the adverse event of iaCT with radiotherapy, and the main advantage of superselective iaCT was not lost.
Impact of adjuvant chemotherapy and cumulative cisplatin dose in locally advanced nasopharyngeal carcinoma (LA-NPC) treated with definitive chemoradiotherapy.
Authors: Oliva Bernal Marc , Huang Shao Hui , Taylor Rachel , Su Jie , Xu Wei , Hansen Aaron Richard , Jang Raymond Woo-Jun , Bayley Andrew , Hosni Ali , Giuliani Meredith Elana , Ringash Jolie , Bratman Scott Victor , Cho John , Irish Jonathan Crawford , Waldron John , Weinreb Ilan , Kim John , O'Sullivan Brian , Siu Lillian L. , Spreafico Anna
Published: May 2019

6046

Background: Total cumulative cisplatin dose (CDDP-D) (concurrent/induction/adjuvant) in multimodality therapy for LA-NPC has been associated with survival at centers in Asia. We evaluated the survival impact of adjuvant chemotherapy (adj chemo) and total CDDP-D in a large, single institution Canadian cohort of LA-NPC. Methods: Patients (Pts) withWHO type II and III LA-NPC treated with concurrent IMRT with high-dose CDDP and adj chemo with CDDP/Carboplatin and 5-FU (maximum total/adjuvant CDDP-D= 540/240 mg/m2) between 2003-2016 were analyzed. EBER status was tested by ISH. Staging was classified by UICC/AJCC7thedition TNM. Kaplan-Meier 5-year (5y) for overall survival (OS) and recurrence-free survival (RFS) were calculated and compared by log-rank test betweenstage, adj chemo (yes vs no) and total CDDP-D (>300 vs ≤300mg/m2). Multivariable analysis (MVA) identified survival predictors. Results: A total of 312 pts were evaluated: median age = 49.8 (range 17.4-75.9); EBER+/-/unknown=67%/1%/32%; stage II/III/IV=2%/51%/47%; T4=36%; N3=17%; adj chemo=83% (21% switched to carboplatin); median total/adjuvant CDDP-D=380/160 mg/m2; median follow-up 7.6 years (range 0.6-14.9). 5y OS differed by stage II-III vs IV (95% vs 80%, p<0.001) and total CDDP-D >300 vs ≤300mg/m2 (89% vs 83%, p=0.02). Adj chemo and total CDDP-D impacted 5y OS in stage IV (table). 5y RFS was higher in stage IV with total CDDP-D >300 vs ≤300mg/m2 (74% vs 59%, p=0.03), with a trend in locoregional control (LRC) (91% vs 80%, p=0.05) but not significant on distant control (DC) (78% vs 72%, p=0.36). Conclusions: Total CDDP-D >300 mg/m2 impacts OS in the overall cohort. The benefit of adj chemo and total CDDP-D on OS and RFS is significant in stage IV but not stage II-III LA-NPC, mainly due to higher LRC rather than DC. [Table: see text]
Pretreatment obesity prolongs survival in elderly patients (≥65 years) with head and neck cancer (HNC).
Authors: Desai Parth Anil , Kakarla Sushanth , Saksena Annapurna , Choi Byeongyeob , Goros Martin , Miller Frank R. , Karnad Anand B. , Cervantez Sherri Rauenzahn
Published: May 2019

6052

Background: Pre-treatment Body mass Index (BMI) is an important prognostic factor in HNC with variable survival benefit reported till date. Despite increasing incidence of HNC in geriatric patients there is limited information on prognostic variables in this group. Methods: This is a single center, retrospective cohort study of patients with HNC≥65 years of age at their diagnosis from 2012 to 2016. Patients were stratified by BMI (Class 1- BMI<25 kg/m2 (underweight & normal), Class 2- BMI≥25-29.9 kg/m2 (overweight), Class 3- BMI≥30 kg/m2 (obese) ). Various variables were collected & appropriate statistical analysis was done. Results: 188 elderly HNC patients with non-metastatic disease were stratified into three BMI groups (Table) & found to have evenly distributed co-variates. The Median OS was significantly higher in class 3 patients (53 months) compared to class 1 (21 months) (p =0.02). In multivariate analysis, class 3 was an independent good prognostic indicator (Hazard ratio=0.44;Range-0.21-0.90, p=0.03). Stage, CCI score & gastrostomy tube were adverse prognostic factors in the study. Conclusions: Obese elderly HNC patients have survival benefit over normal/underweight patients. Predictive prognostic models incorporating BMI with other prognostic factors are needed to determine appropriate management in these patients. [Table: see text]
Immune signatures associated with response to neoadjuvant PD-1 blockade in oral cavity cancer.
Authors: Knochelmann Hannah , Horton Joshua Dean , Meek Megan , Krieg Carsten , Timmers Cynthia Dawn , Romeo Martin , Wrangle John M. , Rubinstein Mark P. , Young M Rita I , Neskey David , Paulos Chrystal
Published: May 2019

6055

Background: PD-1 inhibition therapy has revolutionized clinical medicine as it can mediate durable responses in a small cohort of patients. Yet, it remains incompletely understood why these patients respond. To address this question, we studied patients with oral cavity squamous cell carcinoma (OCSCC) to elucidate immune phenotypes associated with response to nivolumab. Methods: We defined the immune profile from the blood and tumor of patients on neoadjuvant nivolumab. We tested if tumor-infiltrating lymphocytes (TIL) could be preferentially expanded ex vivo from nivolumab-responsive patients versus those who were either non-responsive or had never received nivolumab. During the course of therapy, we comprehensively profiled a number of surface markers on patients’ T cells to define their activation status, cytotoxic capacity and memory phenotype. Moreover, the immune profile of the peripheral blood was assessed pre- and post-nivolumab using high dimensional mass cytometry. Results: Regardless of PD-1 therapy, TIL were successfully expanded from 11 of the 12 patients. TIL were comprised of both CD4+ and CD8+ T cells. Additional investigation revealed that the frequency of CD4+ T cells and effector memory T cells in TIL correlated with disease progression (CD4: p = 0.04, r = 0.74, effector memory: p = 0.046, r = 0.74). TILs from responders expressed higher CD26 (p = 0.007, r = -0.88) and Tim3 (p = 0.045, r = -0.74) while PD-1, Lag3, and Ox40 were not differentially expressed based on response. Spearman correlation and Mann Whitney U test were used to assess phenotypic differences. Conclusions: We demonstrate, for the first time, that TIL can be reliably expanded from OCSCC patients on neoadjuvant nivolumab. Moreover, individuals who were responsive to PD-1 blockade had TIL expressing high levels of CD26 and Tim3. Future studies will explore if these markers are predictive of responses and if they contribute to treatment outcome.
Safety and disease control achieved with the addition of nivolumab (Nivo) to chemoradiotherapy (CRT) for intermediate (IR) and high-risk (HR) local-regionally advanced head and neck squamous cell carcinoma (HNSCC): RTOG Foundation 3504.
Authors: Gillison Maura L. , Ferris Robert L. , Harris Jonathan , Colevas A. Dimitrios , Mell Loren K. , Kong Christina , Jordan Richard C. , Moore Kevin , Truong Minh Tam , Kirsch Claudia , Clump David Anthony , Ohr James , He Kai , Blakaj Dukagjin , Deeken John F. , Machtay Mitchell , Curran Walter John , Le Quynh-Thu
Published: May 2019

6073

Background: Nivo, which inhibits the programmed death-1 (PD-1) receptor, improved survival for pts with platinum-refractory recurrent/metastatic HNSCC. A clinical trial evaluated the safety of adding nivo to 4 standard intensity modulated (chemo) radiotherapy (RT) regimens (see table) for pts with newly diagnosed IR/HR HNSCC. Primary endpoint was safety and feasibility. Methods: Eligibility included IR (p16+ oropharynx [op], T1-2N2b-N3/T3-4N0-3, >10 pack-years [pys], or T4N0-N3/T1-3N3, ≤10 pys) & HR HNSCC (oral cavity, larynx, hypopharynx, p16- op, T1-2N2a-N3/T3-4N0-3). 10 pts/arm (8 evaluable; 0-2/8 DLTs acceptable). Nivo (dose & schedule varied per arm) started 2 wks pre-RT & continued 3 months post-RT. Feasibility of adjuvant nivo months 3-12 post-RT defined as ≥4 of 8 pts/arm received 7 doses. Arm 4 limited to age ≥70, Zubrod performance status (PS) 2, CrCl <50 ml/min, grade ≥2 hearing loss or ≥ grade 3 neuropathy. Results: Characteristics of 39/40 treated pts: median age 62, 79% male, 49% PS0, 38% HR, 67% >10 pys, 62% p16+ op, 72% T3-4, 85% N2-3. Grade ≥3 nivo-related AEs: adrenal insufficiency, diarrhea-3, anemia, fatigue-2, mucositis-3, nausea, vomiting, lipase increase-6, amylase increase-2, lymphocyte/neutrophil/WBC decrease-4, hyponatremia-3, anorexia, maculo-papular rash. SAE in 4/10, 4/9, 5/10 & 4/10. DLTs, adjuvant chemo feasibility, median follow-up (mo), progression or death events per arm shown in table. Conclusions: Nivo concomitant with all (chemo)RT regimens was safe for patients with newly diagnosed IR/HR HNSCC but adjuvant nivo was infeasible after high-dose cisplatin or in cisplatin-ineligible patients ( NCT02764593 ). Preliminary data on progression/death is provided. Acknowledgements: Support for this study was provided by Bristol-Myers Squibb Company. Clinical trial information: NCT02764593. [Table: see text]
Cost-effectiveness analysis of chemoradiation compared to radiation alone in the treatment of nonmetastatic oropharyngeal cancer.
Authors: Albarmawi Husam , Onukwugha Ebere , Cullen Kevin J. , Goloubeva Olga G.
Published: May 2019

6075

Background: Using concurrent chemoradiation (CRT) to treat oropharyngeal cancer (OPC) has increased since 2000. However, there is limited information regarding the cost-effectiveness of CRT compared to radiation alone (RT) especially given the approval of cetuximab (cetux) in 2006. We conducted a cost-effectiveness analysis of 1) platinum-based CRT compared to RT and 2) cetuximab plus RT (cetux+RT) compared to RT to determine the value of CRT over time. Methods: In this retrospective cohort study, we identified non-metastatic OPC patients aged 66 years or older diagnosed between 2000-2011 using the linked Surveillance, Epidemiology and End Results -Medicare dataset. We defined two cohorts based on the diagnosis period: 2000-2005 (Cohort I) and 2006-2011 (Cohort II). Cetux+RT was identified in Cohort II only. We matched the platinum-based CRT and cetux+RT groups to the RT groups using propensity score models that included age, race, marital status, income, Charlson Comorbidity Index and stage at diagnosis. The outcomes were incremental cost, incremental life-year gained (LYG) and incremental cost-effectiveness ratio (ICER) during the 3 years after diagnosis. Costs were estimated from the Medicare perspective and using 2017 USD. Results: 2,646 OPC patients were eligible for the study. The estimated parameters with the corresponding 95% confidence intervals (CI) are shown in the table. Conclusions: From 2000-2005, platinum-based CRT was a cost-effective option compared to RT. From 2006-2011 and compared to RT, platinum-based CRT provided a survival benefit at higher costs while cetux+RT patients incurred higher costs with no survival benefit. [Table: see text]