bluuebunny/crossref_metadata_2025 huggingface dataset:
A loss of microRNA expression as a characterization of synchronous peritoneal secondary localizations of epithelial ovarian cancer as compared to primary tumors.
Authors: Mezzanzanica Delia , De Cecco Loris , Califano Daniela , Losito Simona , Bagnoli Marina , Franco Renato , Scognamiglio Giosuè , Chiappetta Gennaro , Lorusso Domenica , Raspagliesi Francesco , Canevari Silvana , Pignata Sandro
Published: March 2020

11037

Background: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy and one of the most challenging areas of cancer research being a highly heterogeneous disease difficult to diagnose and treat. EOC has a peculiar dissemination process due to the sloughing-off of cells from primary tumors and their spread throughout the peritoneal cavity. A better characterization of the mechanism involved in tumor spreading might help in design new therapeutic intervention. Methods: Forty-four couples of chemo naïf primary tumors and synchronous secondary peritoneal localizations, obtained at primary surgery from MITO2 clinical trial, have been profiled for microRNA (miRNA) expression on an Agilent Platform. Total RNA was extracted from formalin-fixed paraffin embedded tissues. An independent validation set of samples with similar characteristics, has been collected at INT Milan. Results: By class comparison analysis, imposing a false discovery rate <10%,45 miRNAs were identified as differentially expressed: 32 down-modulated and 13 up-modulated in secondary localizations compared to primary tumors. Among the miRNAs down-modulated in the secondary localizations we detected most of the miRNA belonging to the Xq27.3 cluster, whose low expression we previously described to be associated with EOC early relapse, and a number of miRNAs related to epithelial/mesenchimal transition (EMT) whose modulation could be related to dissemination of the disease and response to drug treatment. In particularly loss of has-miR-506 resulted associated to platinum resistance since its ectopic expression in EOC cell lines increased their sensitivity to the drug. Furthermore preliminary data indicated that has-miR-506 regulated N-cadherin linking its modulation to EMT. Conclusions: To our knowledge, the present study is the first attempt to characterize a miRNA signature differentially expressed between EOC primary tumors and synchronous secondary peritoneal localizations. The validation of the miRNA profile as well as of target genes might help in elucidating EOC dissemination mechanisms and in defining possible new therapeutic targets.
Reliability of prognostic and predictive factors evaluated by needle core biopsy for breast cancer in large tumors.
Authors: Petrau Camille , Clatot Florian , Berghian Anca , Veresezan Liana , Cornic Marie , Baron Marc , Callonnec Francoise , Veyret Corinne , Laberge Sophie , Picquenot jean-Michel
Published: March 2020

1104

Background: Preoperative needle core biopsy (NCB) in breast cancer allows both invasive carcinoma diagnosis and the assessment of the main prognostic/predictive markers. However, large tumors, which may be candidates for preoperative chemotherapy, are potentially more heterogeneous than small ones, and the reliability of these factors measurements by NCB in these cases has been less documented than in whole surgical specimens (SS). The aim of this study was to evaluate the correlation for the main histological and immunohistochemical (IHC) features between NCB and SS in large tumors (>2cm), and to assess major discordances that may impact the therapeutic decisions. Methods: All patients treated in our center for newly diagnosed early breast cancer between January 2008 and December 2011 were retrospectively screened. Large tumors for which both NCB and SS were available were included. Patients treated by preoperative chemotherapy were excluded. The assessed histological and IHC parameters were histological type, SBR grade, estrogen (ER) and progesterone receptors (PR) expression, HER2 status (completed by CISH if needed), intrinsic subtype, and proliferation markers (mitotic activity index (MAI), Ki67). All samples were independently read twice. Comparisons were performed using Kappa test. Results: 163 pairs of NCB-SS were analyzed. Average pathological tumor size was 3.2cm. Correlation was excellent for ER and HER2 (k=0.98 and 0.91 respectively), good for histological type (k=0.74), PR (k=0.79) and intrinsic subtype (k=0.73), but poor for Ki67 (k=0,60), SBR grade (k=0.29) and MAI (k=0.24). Among major discordances, 6 tumors were graded SBR I on NCB but SBR III on SS; 1 tumor was negative for ER on NCB but positive on SS. Importantly, 3 of the 21 HER2 positive cases (14%) were negative after CISH on NCB but positive on SS. Conclusions: Diagnostic NCB in large early breast tumors allows reliable determination of hormonal receptors expression, histological type and intrinsic subtype. SBR grade may however be deeply underestimated by this method, and false negative evaluation of the HER2 status in 14% of HER2 positive patients would have led to a detrimental lack of trastuzumab administration.
The usefulness of UGT1A1 polymorphism testing before starting irinotecan-based chemotherapy.
Authors: Harada Taishi , Saito Haruhiro , Sugiura Makiko , Murakami Shuji , Kondo Tetsuro , Oshita Fumihiro , Yamada Kouzo
Published: March 2020

11055

Background: A few studies have revealed an association between UGT1A1 genotype and irinotecan-induced neutropenia. However, the usefulness of UGT1A1 polymorphism testing before starting irinotecan-based chemotherapy is controversial, even now. We assessed the clinical usefulness of UGT1A1 polymorphism testing before chemotherapy. Methods: 136 lung cancer patients were treated with nedaplatin and irinotecan combination chemotherapy as initial chemotherapy. Except for the patients with low enzyme activity of UGT1A1, 70 patients were treated after UGT1A1 polymorphism testing. (test group) 66 patients were treated without UGT1A1 polymorphism testing. (non-test group) We retrospectively analyzed adverse events and compared the test group with non-test group. Results: We could not confirm any reduction in hematologic or non-hematologic toxicity statistically in the test group. In 9 patients with non-hematologic toxicity of grade 4 and 5, 6 patients had febrile neutropenia (FN). All patients with FN were older than 70 years old. Adverse events in elderly patients were significantly more frequent than in the non-elderly. Conclusions: In patients treated with nedaplatin and irinotecan combination chemotherapy, UGT1A1 polymorphism testing before starting chemotherapy did not reduce adverse events. With UGT1A1 polymorphism testing only, it was difficult to predict the onset of severe adverse events. Therefore, it is more important to manage adverse events carefully, especially in elderly patients.
PIK3CA mutations in primary HER2-positive and triple negative breast cancer.
Authors: Loibl Sibylle , Denkert Carsten , Loi Sherene , Andre Fabrice , Mueller Berit , Schneeweiss Andreas , Blohmer Jens U. , Jackisch Christian , Sanxing Guo , Gade Stephan , Fasching Peter A. , Schem Christian , Sotiriou Christos , Untch Michael , Von Minckwitz Gunter
Published: March 2020

11061

Background: Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in breast cancer (BC), PIK3CA mutations being the most common. Mutations are frequently found in hot-spots located in the helical and kinase domains (exons 9 and 20). Reported data is discrepant with regard to prognostic or predictive value of PIK3CA mutations especially in HER2+ve BC. We therefore investigated the frequency and prognostic associations of PIK3CA mutations in HER2+ve and triple negative (TN) primary BC by treated with neoadjuvant therapy. Methods: We prospectively evaluated PIK3CA mutations in the 595 participants of the neoadjuvant Geparsixto study (NCT01426880). The study investigates the effect of adding carboplatin to a liposomal doxorubicin/taxane combination for the treatment of patients with HER2+ve and TN primary BC. All HER2+ve patients received trastuzumab and lapatinib, the TN patients received bevacizumab. HER2, hormone receptors (HR), and Ki67 were centrally assessed. PIK3CAwas genotyped in tumor material from formalin-fixed, paraffin embedded core biopsies taken before therapy using classical Sanger sequencing of exon 9 and 20. Results: From 09/2011 to 11/2012, 595 patients with HER2+ve or TN primary BC have been randomized in the Geparsixto study. Median age was 47 years (range 21-78); most tumors were cT2 (65%); cN0 (57%); ductal invasive (93%), grade 3 (65%); within the HER2+ve group 28% were HR positive. So far, PIK3CA genotype was evaluated in 395 randomized patients - 176 with HER2+ve and 219 with TN disease. Overall, 11.1% were found to have at least one mutation, in HER2+ve: 18.2% and TN BC: 5.5%. An exon 9 mutation was detected in 6.3% of the HER2+ve and 2.7% of the TNBC cases and an exon 20 mutation in 11.9% of the HER2+ve and 3.6% of the TN cases. A mutation in both exons was detected in 2 TN cases. PIK3CAmutations were more frequent in the HER2+ve/HR+ve compared to the HER2+ve/HR-ve group: 22.8% vs 10.6% respectively (p=0.047). Conclusions: PIK3CAmutations are more frequent in HER2+ve then in TN BC which is in line with previous reports. Results on all 595 patients and the correlation with response to therapy (pCR) will be presented at the meeting. The project has been funded within the EU-FP7 project RESPONSIFY No 278659. Clinical trial information: NCT01426880.
Correlation of ERCC1 mRNA expression with KRAS mutation status in colorectal, pancreatic, and lung adenocarcinoma.
Authors: Hanna Diana L. , Maus Martin K. H. , Stephens Craig , Grimminger Peter Philipp , Astrow Stephanie H. , Yang Dongyun , Loupakis Fotios , Hsiang Jack , Zeger Gary , Barzi Afsaneh , Lenz Heinz-Josef
Published: March 2020

11062

Background: KRAS is mutated in about 40% of colorectal cancers; it is the only validated predictive marker used in patients with metastatic disease. ERCC1 is a critical enzyme in nucleotide excision repair and is associated with response, progression free and overall survival in patients with NSCLC, colorectal, and gastric cancer treated with platinum based chemotherapy. We tested whether ERCC1 mRNA expression correlates with KRAS and BRAF mutation status in patients with colorectal, pancreatic, and lung cancer. Methods: Formalin fixed paraffin embedded tumor specimens from 1,514 patients (573 colorectal; 91 pancreatic; 850 lung) were microdissected; DNA and RNA were extracted. Specifically designed primers and probes were used to detect 7 different base substitutions in codons 12 and 13 of KRAS and the V600E BRAF mutation. ERCC1 mRNA expression levels were measured by quantitative RT-PCR in a CLIA approved laboratory. Results: Mt KRAS tumors had significantly lower ERCC1 mRNA levels relative to wt KRAS tumors in both colorectal (0.89 vs. 1.06; p<0.001) and pancreatic (1.20 vs. 1.80; p=0.006) groups. While mt KRAS lung tumors showed decreased ERCC1 expression (1.25 vs. 1.39), the trend did not meet significance (p=0.069). Within the colorectal subset, mt BRAF cancers trended towards less ERCC1 expression than tumors harboring both wt KRAS/BRAF genes (0.96 vs. 1.06; p=0.25). Conclusions: This is one of the first reports linking KRAS mutation status with ERCC1 gene expression in colon, pancreatic and lung cancer. KRAS mutation status may predict sensitivity to platinum based therapy in colon and pancreatic cancer. Colorectal tumors with either the BRAF or KRAS mutation have decreased ERCC1 expression, relative to those that carry both wildtype genes. This may explain the poor sensitivity to oxaliplatin based regimens in these patients. Furthermore, this suggests that ERCC1 expression may be driven by MAPK activation given the uniform ERCC1 downregulation amongst mt KRAS and mt BRAF cancers. Thus, MEK inhibitors may improve the efficacy of oxaliplatin based chemotherapy. Prospective biomarker driven studies should validate these principles, guide clinical decision making and improve outcomes.
Ribonucleotide reductase subunit-2 (RRM2) and thymidylate synthase (TS) to predict shorter survival in patients (pts) with resected stage I-III non-small cell lung cancer (NSCLC).
Authors: Grossi Francesco , Dal Bello Maria Giovanna , Savarino Graziana , Salvi Sandra , Puzone Roberto , Pfeffer Ulrich , Fontana Vincenzo , Rijavec Erika , Barletta Giulia , Genova Carlo , Sini Claudio , Ratto Giovanni Battista , Truini Mauro , Merlo Domenico Franco
Published: March 2020

11063

Background: Tumor biomarkers can help to identify pts with early-stage NSCLC with high risk of relapse and poor prognosis. The aim of this study was to investigate the prognostic value of 7 biomarkers involved in DNA synthesis and repair. Methods: Tumour tissues from 82 radically resected, stage I-III NSCLC pts were consecutively collected to investigate the following biomarkers: excision repair cross-complementation group 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunit 1 (RRM1), ribonucleotide reductase subunit 2 (RRM2), subunit p53R2, thymidylate synthase (TS) and class III beta-tubulin (TUBB3) using immunohistochemistry (IHC) and quantitative real time-polymerase chain reaction (qRT-PCR). Expression levels of these genes were also investigated in a large publicly available NSCLC microarray dataset (Director Challenge Consortium, DCC). Results: RRM2 expression (p=0.031), TS expression (p=0.023), and pathologic stage (p<0.001) were found as independent prognostic factors for shorter survival. The expression of ERCC1, RRM1, p53R2, TUBB3, BRCA1, as well as other clinical characteristics, failed to show any statistically significant association with the survival. Despite the lack of statistical significance, patients with lower RRM2 expression (i.e., ≤ 140) survived longer than pts with higher RRM2 levels (p=0.069). There was a trend towards longer survival for BRCA1-, ERCC1-, RRM1- and TS-negative pts and for p53R2- and TUBB3-positive pts. For all of the biomarkers except TUBB3, the OS trends relative to the protein expression levels were in agreement with those relative to the respective gene expression levels, although the differences were not statistically significant. In the larger DCC dataset, TS (p=0.005), and BRCA1 (p=0.021) were identified as prognostic markers for OS, independent of tumour stage. Conclusions: This study has shown that high RRM2 and TS protein levels are negative prognostic factors for resected, stage I-III NSCLC pts. The data obtained by qRT-PCR confirmed these results. Analysis of the DCC microarray dataset detected TS and BRCA1 as independent prognostic markers of OS.
Inflammatory phenotype of classical (CD14++CD16-) monocytes in patients with advanced non-small cell lung cancer.
Authors: McCarthy Fiona Margaret , Ghirelli Cristina , Zollinger Raphael , Phillips Melissa , Roshani Rozita , Candido Juliana , Trehy Roisin , Sheaff Michael , Steele Jeremy , Hagemann Thorsten
Published: March 2020

11071

Background: Monocytes are intrinsic members of the innate immune system and play an important role in immunity and inflammation. Human monocytes are subdivided into three populations depending on cell surface CD14 and CD16 expression: Classical (CD14++ CD16-), intermediate (CD14+CD16- ) and non-classical (CD14- CD16++). These populations have diverse functions and have been postulated to play both anti and pro-inflammatory roles in a variety of diseases including atherosclerosis, sarcoidosis and other rheumatological conditions. However, the prevalent monocyte populations in cancer have not as yet been identified. We aim to define the prevalent monocyte populations in non-small cell lung cancer as well as further characterising them using flow cytometry and Affymetrix technology. Methods: Blood was obtained from 24 newly diagnosed patients with advanced non-small cell lung cancer and 12 age matched healthy donors. Monocyte subpopulations were sorted using flow cytometry. Gene expression profiling was performed using Affymetrix Human U133 Plus 2.0 array. Results: The classical (CD14++CD16-) monocyte population is significantly increased in non-small cell lung cancer patients when compared to healthy donors (p<0.01). The intermediate (CD14+CD16+) and non-classical (CD14- CD16++) populations are unchanged. Analysis of the gene expression profile of the classical monocyte subset identified 265 up-regulated and 261 down-regulated genes in cancer patients compared to healthy donors (p<0.05, fold change >2). These genes were assigned to biological processes with gene ontology annotation. Functional annotation reveals a strong association of regulated genes with the G.O term “inflammation” (p=0.009). Among these inflammatory genes are a cluster of chemokines including CXCL2 and CXCR4. Conclusions: By identifying the prevalent monocyte subsets as well as characterising their function in cancer, there is the potential to target detrimental effects and promote their beneficial functions. As such, monocytes subsets may be used as a possible therapeutic target.
Cancer-testis antigens in triple-negative and locally advanced breast cancer.
Authors: Harris Samuel John , Turner Natalie Heather , Chionh Fiona J.M. , Walkiewicz Marzena , Chakrabarti Anannya , Deb Siddhartha , Cebon Jonathan S. , White Shane , John Tom
Published: March 2020

11072

Background: Cancer-Testis Antigens (CTAs) are immunogenic molecules that have increased expression in triple negative breast cancers (TNBC), a phenotype that whilst associated with poorer survival, is chemosensitive. We investigated expression of the CTAs MAGE-A, MAGE-C1, and NY-ESO-1 in women with Locally Advanced Breast Cancers (LABC) and TNBC to determine the association between CTA expression, survival and response to chemotherapy. Methods: We reviewed patient charts, treated for either TNBC or LABC between 1997 and 2011. Tissue samples were used for immunohistochemical (IHC) staining for MAGE-A, MAGE-C1 and NY-ESO-1 and compared using Fisher’s exact test. Positive expression was defined as any antigen staining above background.. Clinicopathological features were correlated with IHC results and survival estimated using the Kaplan Meier method. Results: A total of 106 cases were investigated (64 TNBC and 42 LABC). In the TNBC cohort the median age was 58 and TNM stages 1 to 3c. CTA expression occurred in 56, 51 and 43% for MAGE-A, MAGE-C1 and NY-ESO-1 respectively. CTA expression was not associated with overall survival (OS) or time to progression. In the LABC cohort the median age was 54 and consisted of stage IIIb tumors. All breast cancer subtypes were represented. CTA expression occurred in 26, 64 and 21% for MAGE-A, MAGE-C1 and NY-ESO-1 respectively. There was no association between CTA expression and response to chemotherapy. In a univariate analysis MAGE-A expression in the LABC group was associated with poorer OS (median 25 vs 76 months, HR 3.347 95% CI 1.44 to 21.68, p=0.015). However, there were more TN patients and Grade 3 tumors in the MAGE-A positive group. Across the two groups, MAGE-A (51 vs 14% p=0.002) and NY-ESO-1 (37 vs 2% p=0.006) but not MAGE-C1 had significantly higher expression in ER -ve tumors. There was higher expression of MAGE-A (51 vs 25% p=0.025) and NY-ESO-1 (43 vs 10% p=0.002) in Grade 3 tumors. Conclusions: MAGE-A, MAGE-C1 and NY-ESO-1 are highly expressed in TNBC and high-grade subsets of early breast cancer. CTA expression in TNBC was not predictive of survival nor response to chemotherapy in LABC. However, MAGE-A expression was found to be associated with poorer overall survival in LABC.
Clinical significance of programmed death ligand-1 expression in non-small cell lung cancer (NSCLC).
Authors: Velcheti Vamsidhar , Schalper Kurt , Carvajal Daniel , Chen Lieping , Sznol Mario , Gettinger Scott N. , Herbst Roy S. , Rimm David
Published: March 2020

11075

Background: Programmed cell death ligand-1 (PDL1) is expressed on various human cancers and is a major mechanism for immune evasion. Preliminary evidence suggests that PDL1 expression on cancer cells predicts response to anti-PD-1 therapy. Here we report our findings using automated quantitative immunofluorescence (QIF) to determine the frequency and prognostic value of PDL1 in two independent NSCLC cohorts. Methods: Five antibodies against PDL1 were screened for sensitivity and specificity using PDL1 transfected cells, normal human placenta and tonsil. Only one monoclonal antibody (clone 5H1) met criteria for specificity. This antibody was used to assess two cohorts of NSCLC cases in TMAs. The cohorts represented 204 cases from Yale University and 340 cases from hospitals in Greece. PDL1 protein was measured using QIF analysis using AQUA method. In addition, in-situ PDL1 mRNA levels were measured in the Greek cohort using the RNAscope paired-primer assay with AQUA method. Results: PDL1 protein expression was detected in 25% and 36% of the studied cohorts, respectively. PDL1 positivity was significantly associated with the presence of tumor-infiltrating lymphocytes (TIL) in both series. Patients with PDL1 protein positivity had better outcome in both series (Log Rank: p=0.036 for Yale cohort, p=0.027 for Greek cohort). Multivariate analysis showed that PDL1 expression was associated with better outcome independent of histology, presence of TILs, and stage in the Greek cohort and marginally significant in the Yale cohort. These findings were further validated by the PDL1 in-situ mRNA measurement in the Greek cohort. PDL1 protein and mRNA levels showed a positive non-linear relationship (R2=0.14, P<0.001). Positive PDL1 mRNA was found in 53% of patients with NSCLC and was also associated with the presence of TILs and longer overall survival (31 vs. 43 months, p=0.017). Conclusions: Tumor PDL1 protein positivity is detected in 25-30% of NSCLCs and associates with increased TILs and better outcome. Elevated PDL1 mRNA occurs in a higher proportion of NSCLC cases and provides comparable prognostic information. Measurement of in situ PDL1 protein and mRNA could be of more clinical value than either method alone.
Intraoperative radiotherapy in early breast cancer: 400 consecutive patients in one institution.
Authors: Steiner Mariana , Leviov Michele , Biterman Arie , Shiloni Eitan , Goldman Jehudit
Published: March 2020

1108

Background: From 2006 we offer intraoperative radiotherapy as the only post lumpectomy breast irradiation as an alternative to the standard post-operative WBRT in low risk early breast cancer patients (age > 60, invasive ductal carcinoma < 2 cm and clinically negative axilla). Younger patients (>50) or patients with tumors up to 3.5 cm or other histologies are treated too if they are not candidate for standard local therapy. In patients found to have high risk tumor characteristics at final pathology, additional local breast therapy is considered. Methods: Intrabeam System is used administering 20 Gy at the surface of surgical cavity. Results: 400 patients were treated. Their median age was 70 years (55-90). Median clinical tumor size was 12 mm (5-30). 14.5% had mild to moderate local complications: 6.5% wound infection, 5.8% complicated seromas, 1.7% bleeding or hematoma and 0.5% small skin necrosis. 6.2% experienced major complications: 2.5% required surgical intervention, 2% had late healing (> 90 days), 1% required IV antibiotics and 0.7% had grade III RTOG fibrosis. Median pathologic size was 14 mm (1-40). Pathologic free margins > 1mm were obtained in 98.8% of patients. 15.5 % were found to have axillary l-nodes involved (11% one node only), 12% of patients had adverse unexpected breast pathologic findings (7.5% EDCIS or LVI) and 11% had additional local therapy, most of them WBRT. Median follow up is 30 months (1-76) in the whole group and 43 months (3-76) in the first 200 patients treated. Seven ipsilateral breast failures (1.7%) and one axillary recurrence were observed, all had radical local therapy. Four patients developed systemic disease (1%), one of them with simultaneous breast recurrence and one had contralateral breast cancer. Conclusions: We conclude that intraoperative radiotherapy using the Intrabeam system is feasible and may offer an alternative to whole breast RT in low risk breast cancer patients. Clinically significant local morbidity rate is low and self limiting. Longer follow up is needed to evaluate final results and late toxicity.
Molecular tumor profiling (MTP) of poorly differentiated neoplasms (PDN) of unknown primary site.
Authors: Greco F Anthony , Spigel David R. , Hainsworth John D.
Published: March 2020

11080

Background: The inability to definitively determine the lineage of neoplasms is less common with modern immunohistochemistry (IHC) and genetic profiling. Nonetheless some PDN defy lineage classification by extensive standard pathologic evaluation. The advent of MTP may provide a new method of improving the diagnosis of these challenging cancers. Methods: A total of 30 of 751 (4%) patients (pts) seen from 2000 – 2012 with cancer of unknown primary (CUP) had PDN without a definitive lineage determined by IHC (median 18 IHC stains, range 9 – 51). From 2008 – 2012 the 30 biopsies had MTP (RT-PCR mRNA CancerTYPE ID, bioTheranostics, Inc.). Additional IHC, genetic sequencing, fluorescent in situ hybridization for specific chromosomal changes and repeat biopsies were performed when feasible to support the MTP diagnosis, and clinical features correlated. Results: MTP lineage diagnoses were made in 25 of 30 (83%), including 10 carcinomas (3 germ cell, 2 neuroendocrine, 5 others), 5 melanomas, 8 sarcomas (3 peritoneal mesothelioma, 1 PNET) and 2 hematopoietic neoplasms (1 lymphoma, 1 chloroma). Additional IHC, genetic testing [BRAF, i(12)p] or repeat biopsies confirmed the MTP diagnoses in 11 of 15 tumors, and the clinical features were consistent with the MTP diagnoses in the majority of patients. Conclusions: This MTP assay can frequently provide a diagnosis for CUP pts and PDN without a definitive lineage defined by extensive IHC. The earlier application of MTP will likely provide an expedited diagnosis, and for some neoplasms is the only test capable of defining lineage and a more specific diagnosis. Appropriate therapy, particularly for pts with germ cell tumors, melanoma, and lymphoma depends on a specific tissue of origin diagnosis.
Diffusion-weighted imaging using ADC mapping as an imaging biomarker for breast cancer invasiveness.
Authors: Bickel Hubert , Bogner Wolfgang , Dubsky Peter Christian , Bartsch Rupert , Rudas Margaretha , Helbich Thomas , Pinker-Domenig Katja
Published: March 2020

11093

Background: Recently, functional imaging techniques such as diffusion weighted imaging (DWI) have been added to routine MR and have shown great potential for improving breast cancer diagnosis. DWI depicts cellular diffusivity on a molecular level and can be quantified using the apparent diffusion coefficient (ADC). In malignant tumors diffusivity is restricted, leading to lower ADC values than benign tumors. The aim of this study was to proof, that DWI can be used to differentiate benign from malignant tumors and to elucidate if ADC can serve as an imaging biomarker for breast cancer invasiveness. Methods: In this IRB-approved study 250 patients with 267 suspicious breast lesions (BI-RADS IV-V) were included. All patients underwent routine MR at 3T. A DWI-sequence was added to a standard imaging protocol, increasing measurement time by 2:30 min. The lesions were identified in routine MR and DWI sequences and ADC values of the lesions were calculated. Histopathology was used as the standard of reference for all lesions. Appropriate statistical tests were used to compare the ADC values of benign and malignant tumors (cut-off value 1.25×10-3mm²/s), of invasive and non-invasive disease and between different invasive tumor subtypes. Results: There were 91 benign (mean ADC 1.58×10-3mm²/s) and 176 malignant (.94×10-3mm²/s) lesions, sensitivity and specificity were 94.3% (PPV 95.4%, CI 0.91-0.98) and 91.2% (NPV 89.2%, CI 0.81-0.94). 155 lesions were invasive cancers (median ADC .90×10-3mm²/s), while 21 were non-invasive ductal carcinoma in situ (1.22×10-3mm²/s). The invasive cancers were 130 invasive ductal (median ADC .91×10-3mm²/s) and 25 invasive lobular cancers (.83×10-3mm²/s). ADC was significantly different between benign and malignant lesions (p<.001) and between invasive and non-invasive cancers (p<.001), while no significant difference could be found between the invasive cancer subtypes (p=.163). Conclusions: Diffusion-weighted imaging reliably allows differentiation of benign and malignant breast tumors. The data suggest that ADC can be used as a non-invasive imaging biomarker for breast cancer invasiveness and may be of importance to treatment planning and outcome in breast cancer patients.
Clinical next generation sequencing (NGS) of fine needle aspiration (FNA) biopsies in non-small cell lung (NSCLC) and pancreatic cancers.
Authors: Hawryluk Matthew J. , Ross Jeffrey S. , Sheehan Christine E. , He Jie , Young Geneva , Otto Geoff , Yelensky Roman , Lipson Doron , Palmer Gary A. , Stephens Phil , Miller Vincent A.
Published: March 2020

11100

Background: FNA is a common diagnostic procedure for the evaluation of pulmonary and pancreatic masses. We sought to determine whether NGS could be performed on these small specimens and to characterize heterogeneity across classes of genomic alterations (GA) in a subset of paired FNA and matched resected primary tumors. Methods: DNA was isolated from formalin fixed paraffin embedded (FFPE) sections of FNA cell blocks using 40µm total sections for NSCLC and 20µm total sections for pancreatic cancers in a CLIA-certified lab (Foundation Medicine). DNA sequencing was performed for 3,320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on indexed, adaptor ligated, hybridization-captured libraries to a median depth of 931x for the NSCLC and 416x for the pancreatic FNAs. Results: Genomic profiles were successfully generated from 19/19 of the NSCLC and 22/23 of the pancreatic FNA cases. We found 97 GA in the 19 NSCLC FNAs (range 2-9, average 5.1 GA per patient). 68% of the patients had GA in TP53 and 21% in KRAS. Only 16% (3/19) patients did not exhibit an actionable alteration. We found 99 GA in the 23 pancreatic cancer FNAs (range 0-12, average 4.3 per patient). 74% of the patients had GA in KRAS. There was 94% concordance of GA found in 4 matched FNA and primary tumor pairs for the pancreatic cases. For the single discordance, manual inspection of the reads of the discordant allele indicated evidence of loss of heterozygosity. Conclusions: NGS can be reliably performed on small FNA samples processed into cell blocks, and the GA discovered significantly correlates with the GA found in matched primary tumors. This study demonstrates the feasibility of NGS in analyzing FNA samples and further broadens the spectrum of commonly encountered specimen types to which this approach can be successfully applied.
Comparison of in vivo skin and in vitro blood lymphocyte models for the prediction of late normal tissue responses in breast radiotherapy (RT) patients.
Authors: Chua Melvin , Somaiah Navita , Davies Sue , Gothard Lone , Rothkamm Kai , Yarnold John
Published: March 2020

11116

Background: Critical opinions for the lack of success of DNA double-strand break (DSB) repair as a predictive marker of normal tissue radiosensitivity include the argument that in vitro cellular responses correlate poorly with in vivo responses due to the modifying influence of tissue environment. In this study, we test the hypothesis that a DNA damage assay based on in vivo irradiated skin tissues better predicts clinical responses in human skin, as opposed to the same assay performed in ex vivo irradiated lymphocytes. Methods: DSB levels (24 h post-4 Gy) were quantified using γH2AX/53BP1 immunostaining in irradiated skin tissues and G0 lymphocytes of 35 breast RT patients. Patients were selected on the basis of late RT effects in their breast and individuals with marked or minimal effects were classified as cases and controls, respectively. Risk factors of late effects established from multivariate analyses of outcomes of two breast RT trials were also considered in patient selection. They were 1) total RT dose, 2) RT dosimetry, 3) tumour bed boost, 4) breast size, 5) surgical cavity, and 6) axillary treatment. Results: Clinical parameters were balanced in both patient groups. Residual foci levels in skin epidermis and dermis were comparable between cases (n = 20) and controls (n = 15). Mean foci per cell were 3.29 in cases, 2.80 in controls for dermal fibroblasts (p = 0.07); 3.28 in cases, 2.60 in controls for endothelial cells (p = 0.08); 2.87 in cases, 2.41 in controls for superficial keratinocytes (p = 0.45); 2.32 in cases, 2.35 in controls for basal keratinocytes (p = 0.27). Residual foci levels in lymphocytes were however significantly higher among cases (foci per cell = 12.1) compared to controls (foci per cell = 10.3, p = 0.01). Of the different cell types, only residual foci levels of dermal fibroblasts and lymphocytes correlated with clinical severity (R = 0.722, p < 0.001; 0.593, p = 0.01, respectively). Interestingly, foci levels were not correlated between skin cells and lymphocytes of the same patients. Conclusions: DSB repair of ex vivo irradiated lymphocytes appears to be a better predictive marker of late effects to breast RT than DSB repair of in vivo irradiated skin.
Changes in the biologic markers between primary tumor and ipsilateral breast tumor recurrence after breast conserving surgery: Discordance and prognosis.
Authors: Okumura Yasuhiro , Nishimura Reiki , Nakatsukasa Katsuhiko , Yoshida Atsushi , Masuda Norikazu , Tanabe Masahiko , Shien Tadahiko , Arima Nobuyuki , Komoike Yoshifumi , Taguchi Tetsuya , Inaji Hideo , Ishitobi Makoto
Published: March 2020

1116

Background: Changes in biological markers due to recurrence are clinically experienced in breast cancer. However, the clinical significance is still uncertain, especially after breast conserving surgery. The changes in biological markers between primary tumor and ipsilateral breast tumor recurrence (IBTR) and their correlations with prognosis were investigated, retrospectively. Methods: A total of 117 consecutive patients with IBTR without distant metastases were enrolled in this study. All patients were examined for ER, PgR, HER2 and Ki-67 in both the primary and recurrent tumors. The cases were categorized into 3 groups: patients with Ki-67 values <20%, <50% and ≥50%, and divided into 2 groups according to the IBTR site, same quadrant(SQ)and different quadrant(DQ) from the initial sites. The distant disease-free survival (DDFS) was calculated using the Kaplan-Meier method and evaluated by the log-rank test and multivariate analyses using Cox proportional hazards model. The median follow-up period was 4.8 years after IBTR. Results: The PgR positive rate from the primary tumor to IBTR decreased from 57% to 39% and the Ki-67 values increased significantly from a mean of 17% to 23%. The concordance rate of the subtype was 62%. In the SQ group, the PgR positive rate significantly decreased and the mean Ki-67 values significantly increased, whereas there was no significant difference in the DQ group. In terms of changes by category due to relapse, the discordance rate in Ki-67 was high in the SQ group, and HER2 was high in the DQ group. Regarding DDFS by a change in the categorization, the cases with discordance in Ki-67 values had significantly lower DDFS in the SQ group(5-year DDFS: 75% vs 52%, p=0.04). However, a clear difference was not found in the DQ group. Conclusions: The PgR positive rate decreased while the mean Ki-67 values increased due to IBTR in the SQ group. The categorical discordance in the Ki-67 values was significantly associated with lower DDFS, especially in the SQ group. These findings suggest that the recurrent site and change in the biological markers were clinical significant in the evaluation of the characteristics and treatment in cases with IBTR.
Does radiation therapy increase late cardiac death in patients with left breast cancer?
Authors: Lin Chi , Denniston Kyle A. , Charlton Mary E.
Published: March 2020

1127

Background: The objective of this study was to evaluate the effect of external beam radiation therapy (RT) on late cardiac death (CD) in patients with left breast cancer. Methods: A total of 529,246 patients who were diagnosed with adenocarcinoma of the breast between 1983 and 2004 and survived ≥ 5 years were identified from the SEER database. After excluding patients who were male, had right breast cancer, received brachytherapy or had missing data, 163,894 patients remained. Examined risk factors for CD include age (≤49/50-59/60-69/70-100), race (white/non-white), stage (In situ/local/regional/distant), breast subsite (nipple and areola/inner quadrant/outer quadrant), diagnosis year (1983-1993/1994-2004), surgery status (none/less than mastectomy/mastectomy) and RT. Time to CD was evaluated using the Kaplan-Meier method. A multivariate logistic regression model was used to evaluate factors associated with the use of RT and the Cox Proportional Hazards model was used to evaluate risk factors for CD. Results: A multivariate logistic regression model revealed that patients who received RT tended to be younger, white, more recently diagnosed, have inner quadrant and more advanced disease and undergo less than mastectomy. Median overall survival for patients with RT was significantly longer than those without RT (263 vs. 226 months, Log-Rank p < .0001). RT group had a lower risk of CD than no-RT group (Log-Rank p < .0001). Median time to CD was not reached in either group. The probability of CD was increased with increasing age and stage, and decreased with more recent diagnosis year and after mastectomy. Cox model found RT to be associated with lower probability of CD (HR 0.66, 95% CI 0.62-0.70), after adjusting for age, stage, surgery status and diagnosis year. Race and breast subsite were not associated with CD. Conclusions: Patients with left breast cancer who survived ≥ 5 years and received RT had a lower risk of cardiac death than those who did not. The cause of this difference is unclear but suggests influence from an uninvestigated factor, potentially the increased use of cardiotoxic chemotherapy or other cardiovascular comorbidity in those patients not receiving RT. Continued study, accounting for such factors, is warranted.
Clinicopathologic analysis of a large series of microinvasive breast cancer.
Authors: Leach Joseph W. , Lillemoe Tamera , Krueger Janet
Published: March 2020

1129

Background: Microinvasive breast cancer (Tmic) is defined by the AJCC as extension of cancer cells beyond the basement membrane with no single focus larger than 1 mm. The clinical behavior of this entity is unclear. Most series suggest that prognosis is similar to non-invasive cancer although the literature is mixed. Surgical management typically reflects invasive breast cancer including lymph node sampling. Published incidence of nodal involvement is also variable with some small series reporting incidence as high as 20%. We present a clinicopathologic review of a large series from a community practice setting. Methods: Using the AJCC definition of Tmic, we retrospectively identified all cases treated within Allina Health System from 2001-2011. Inclusion criteria included no prior history of breast cancer and available follow-up data. Data collected included ER/PR and HER2 status (when available), margin status and surgical and adjuvant therapy. Results: 118 eligible cases were identified with a mean follow-up of 3.65 years and mean age of 56.8 years (34-88). 39 were triple negative and 29 were HER2+. ER/PR data was available on all cases, HER2 on 60. 72 were treated with mastectomy. All patients underwent axillary staging. Lymph node metastasis was identified in 2 cases (one triple negative, one HER2+). In one case the metastasis measured 0.25 mm, in the other 0.4 mm. Complete axillary dissection performed on both cases demonstrated no additional lymph node involvement. Isolated tumor cells were also identified in 9 cases. 2 cases developed local recurrence following lumpectomy and radiation, both in the ipsilateral breast. One recurred with microinvasive disease, the second with DCIS only. There were no cases of metastatic recurrence and no breast cancer associated deaths. Conclusions: The clinical behavior of microinvasive breast cancer in this series is similar to DCIS. The incidence of lymph node metastasis was low (1.7%) and there were no cases of distant metastasis. Our data supports management of microinvasive breast cancer as a subset of DCIS and suggests that the benefit of routine lymph node sampling is questionable.
Active and passive smoking in relation to lung cancer incidence in the Women's Health Initiative prospective cohort study.
Authors: Wang Ange , Kubo Jessica , Luo Juhua , Desai Manisha , Henderson Michael T , Chlebowski Rowan T. , Tindle Hilary , Chen Chu , Manson JoAnn E , Schwartz Ann G. , Cote Michele L , Wactawski-Wende Jean , Gomez Scarlett Lin , Patel Manali I. , Stefanick Marcia L , Wakelee Heather A.
Published: March 2020

1504

Background: The relationship between both active and passive smoking and lung cancer incidence in post-menopausal women was examined in theWomen’s Health Initiative Observational Study (WHI-OS). Methods: The WHI-OS, a prospective cohort study conducted at 40 U.S. centers, enrolled women ages 50-79 from 1993-1998.Among 93,676 participants, 76,304 women with complete smoking and covariate data comprised the analytic cohort, in which the association of lung cancer incidence with active and passive (childhood, adult home, and work) smoking exposure was studied. Results: Over 10.5 meanyears of follow-up with 901 lung cancer cases, lung cancer incidence was higher in current smokers (HR 13.44, 95% CI 10.80-16.75) and former smokers (HR 4.20, 95% CI 3.48-5.08), compared to never smokers. This relationship was dose-dependent for both current and former smokers. Risk of all lung cancer subtypes, particularly small cell lung cancer (SCLC) and squamous cell carcinoma (SqCC), was higher in smokers. Among never smokers, any passive smoking exposure (HR 0.88, 95% CI 0.52-1.49) and most passive smoking categories did not significantly increase lung cancer risk, compared to no passive exposure; however, passive exposure as an adult at home for >=30 years was associated with increased risk, of borderline significance (HR 1.61, 95% CI 1.00-2.58). Current smokers had an annualized lung cancer incidence rate of 472.9 cases/100,000 person-years, compared to 158.1 for former smokers and 36.2 for never smokers (112.3 overall). Conclusions: To our knowledge, this is the first study to examine both active and passive smoking in relation to lung cancer incidence in a complete prospective cohort of U.S. women. Active smoking is associated with significant increases in incidence of all lung cancer subtypes in post-menopausal women, particularly SCLC and SqCC. Smoking cessation decreases lung cancer risk. Prolonged exposure as an adult at home may be the strongest passive smoking contributor to lung cancer risk in this cohort. The findings support continued need for investment in smoking prevention and cessation, research on passive smoking, and understanding of lung cancer risk factors other than smoking.
MRI volumetric analysis of fibroglandular tissue to assess risk of the spared nipple in BRCA 1/2 patients who are considering prophylactic nipple-sparing mastectomy.
Authors: Baltzer Heather , Alonzo Olivier , Yaffe Martin , Narod Steven , Metcalfe Kelly A. , Warner Ellen , Semple John
Published: March 2020

1507

Background: Prophylactic nipple sparing mastectomy (NSM) in BRCA 1/2 mutation carriers is an option for risk reduction but is controversial over concern that residual fibroglandular tissue (FGT) with malignant potential remains in the spared nipple. Since the volume of FGT in the nipple has not been formally evaluated, the objective of this study is to measure the residual volume of FGT in the spared nipple at a standard retroareolar margin (5mm) and identify sources of variability, including a greater margin and patient factors. Methods: A segmentation protocol was applied to breast MRIs from 105 consecutive BRCA 1/2patients. The MRI segmentation quantified volumes for total breast and nipple FGT. The nipple FGT volume was determined by setting the retroareolar margin (depth on MRI). The proportion of FGT in the nipple with 5mm retroareolar margin relative to the breast was calculated as the primary outcome and compared to 10mm margins. Associations between the proportion of FGT in the nipple (5mm) and patient characteristics were examined using uni- and multivariable analyses. Effect size was measured where appropriate. Results: At 5mm and 10mm retroareolar thickness, residual FGT comprised 0.24% (0.02-0.9%) and 0.42% (0.0.2-01.2%), respectively, of the total breast FGT (p < 0.001, Cohen d = 0.03). Smaller breast volume, lower BMI and parity (p < 0.001, p < 0.009, p < 0.009 respectively) were predictive of greater proportion of residual FGT on univariate analysis, while breast volume and parity were predictive with multivariate (R2 = 0.28, F = 16.5, p < 0.0005). Conclusions: The proportion of FGT remaining in the spared nipple with a 5mm margin is extremely small, suggesting very little added risk over a skin sparing mastectomy. This proportion may be influenced by breast volume and childbearing. Doubling the retroareolar margin statistically increases the proportion, yet this likely does not translate into a clinically meaningful increase and may support a slightly thicker retroareolar margin. Overall, our findings support safety of the current trend toward increased rates of prophylactic NSM performed in the BRCA 1/2 patient population.
Time-related changes in yield and harms of screening breast MRI.
Authors: Pederson Holly Jane , O'Rourke Colin , Bolden Lauren D , Khan Sobia , Yadav Manisha , Lyons Joanne , Shepardson Laura , Rim Alice , Crowe Joseph P. , Grobmyer Stephen R.
Published: March 2020

1508

Background: MRI has been accepted as a useful adjunct to screening mammography in high-risk women. Concerns remain over false positive findings, however, and little is known about harms and yield over time. Such information will help women decide about enhanced surveillance. Methods: Of 350 high risk patients offered MRI screening, 320 underwent 757 screens with a 1.5 Tesla magnet from 2008 to 2012 alternating (q 6 mo.) with digital mammography. Data collected included patient characteristics, mammographic density, estimated lifetime risk, and need for additional imaging and/or biopsy. Harms were defined as second look ultrasounds, US or MRI guided core biopsies, surgical biopsies or recommendation for short interval follow up. Estimates of harms over time were modeled by logistic regression. A significance level of 0.05 was used for all testing. Results: Compliance with MRI screening as recommended was 91% with the first MRI, and was not associated with age, race or level of risk. Harms were highest with the first MRI and decreased significantly with subsequent MRIs. Of 59 biopsies, 7 were malignant. Two were found in MRI 1, 3 in MRI 3 and 2 in MRI 4. Women with biopsies resulting from false positive findings were significantly younger (median age 44.5 as compared with 48; p=0.049) and were more likely to have extremely dense breast tissue (36% vs 17%; p=0.028.) Conclusions: This study of highly compliant high risk patients supports the use of MRI as an adjunct to mammography for early detection. The rate of harmful events decreased over time, yet cancer detection did not. This information is critical in counseling women who are considering annual screening breast MRI, particularly younger women and those with dense tissue. [Table: see text]