bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of gene expression by RNA-seq after single dose of trastuzumab (T) reveals predictors of pathologic complete response (pCR) in HER2-positive early breast cancer.
Authors: Galanina Natalie , Sprecher Emmet , Bossuyt Veerle , Sarkar Sudipa , Krop Ian E. , Winer Eric , Tuck David P. , Bruce Can , Harris Lyndsay
Published: March 2020

10558

Background: The use of a ‘brief exposure’ to single agent T allows the measurement of dynamic changes in the transcriptome that may predict response to T-based combinations. We have shown that most gene expression changes in HER2+ tumors treated with T occur in tumors that ultimately achieve a pCR. Our further analysis suggests several patterns of transcriptional change in pCR tumors suggesting different mechanisms of action of T. RNA-seq analysis provides more in-depth annotation of these mechanisms. Methods: Fresh tumor core biopsies were taken at a 2 week time point after a single dose of T (8mg/m2) from 80 HER2+ early breast cancer patients enrolled on a clinical trial of T>T+C. Nucleic acids were extracted using Qiagen AllPrep and were analyzed with Illumina HT12v3 Beadchip and Illumina 610 QUAD V1 SNP arrays. RNA was also processed for sequencing using the Ovation RNA-Seq System and paired-end sequenced using an Illumina Genome Analyzer IIxRNA-seq data was analyzed with Tophat/Cufflinks. Network analysis was performed with Metacore. Results: Among pCR tumors, distinct patterns of differential expression pre/post T were observed, in both microarray and RNA-seq data. ERBB2 down-regulation was characteristic of pCR in one subgroup by microarray. In this group, differentially expressed genes belonged to interaction networks involved in apoptosis and cell cycle regulation. In contrast, tumors with no change in ErbB2 showed differentially expressed genes that belonged to networks related to chromatin assembly and regulation of immune pathways. NOLC1, RPL41, ZCHHC17, and B2M had altered alternative splicing product distributions in both groups. In the ERBB2 down-regulated group, genes with changed expression were enriched for targets of STAT3 and YY1. Conclusions: RNA-seq and microarray reveal distinct responses in tumors that achieve pCR to T-containing regimens. These methods provide predictive markers for validation in subsequent clinical trials.
EGFR exon 20 insertion mutations: Incidence and clinicopathologic characteristics in U.S. patients with lung adenocarcinoma.
Authors: Arcila Maria E. , Nafa Khedoudja , Chaft Jamie E. , Rekhtman Natasha , Zakowski Maureen Frances , Kris Mark G. , Ladanyi Marc
Published: March 2020

10560

Background: Activating insertion mutations in exon 20 of EGFR are reported in a small subset of lung adenocarcinomas (ADC). In contrast to the classic EGFR mutations, they appear to confer primary resistance to currently approved EGFR tyrosine kinase inhibitors. Their incidence and clinicopathologic features are not well established. Methods: Lung ADCs (n=1500) were screened for major activating mutations in EGFR (exons 19 and 21) and KRAS (exon 2). Negative cases were tested for EGFR exon 20 insertions by a PCR-based sizing assay. Extended testing for additional recurrent point mutations in EGFR, KRAS, BRAF, NRAS, PIK3CA, MEK1 and AKT was performed in all cases by Sequenom mass spectrometry. A subset of cases was also tested for ALK rearrangements by FISH. Results: We identified 32cases withEGFRexon 20 insertions, accounting for 11% of all EGFR mutations. EGFRexon 20 insertions were mutually exclusive with the other genetic alterations tested except for PIK3CA mutations. The incidence was higher among never-smokers (p<0.0001) but there was no association with sex, ethnic origin or stage at diagnosis. Insertions were 3, 6, 9 or 12bp; 9bp insertions were most common (50%, 16/32). Morphologically, 90% of tumors were moderate to poorly differentiated with a predominant mixed ADC phenotype. Conclusions: EGFR exon 20 testing may identify a unique subset of EGFR mutant lung ADCs which is significantly larger than previously reported, making this the third most common type of EGFR mutation after exon 19 deletions and L858R. This population could potentially benefit from alternate targeted therapies, many of which are currently in clinical development.
Correlation of the maximum standardized uptake value for f-18 fluorodeoxyglucose with molecular subtype and survival in advanced breast cancer.
Authors: Jia Zhen , Hu Xi-Chun , Zhang Yingjian , Zhou Min , Wang Biyun , Wang Zhong Hua , Zhang Yongping
Published: March 2020

10567

Background: Tumor glucose metabolism correlates with tumor biology and clinical outcome of breast cancer patients. This prospective cohort study was to explore correlations of 18F-FDG uptake, a surrogate for glucose metabolism, with molecular subtypes in women with advanced breast cancer. Methods: Patients diagnosed as advanced breast cancer were enrolled in the study. PET/CT was performed and the Maximum Standardized Uptake Value (SUVmax) of each lesion was documented as baseline, so was clinical and treatment information. Diagnosis of malignant nature of a lesion was confirmed by pathology or further follow-up. Patients who had got a progressive disease in the efficacy assessment were assigned new treatments as per-institutional guidelines. Results: 244 patients met the criteria and were all put into this analysis. Independent factors for influencing SUVmax value included luminal subtype (p= 0.002), triple-negative subtype (p<0.001), ER status (p= 0.028), Her-2 status (p<0.001), and CEA level (p<0.001). A higher SUVmax was significantly associated with poorer median PFS (6.9 vs. 8.1 months, p=0.040) and OS (13.8 vs. 16.9 months, p=0.003). Cox Regression analysis showed that SUVmax value, previous treatments, subsequent treatments and treatment efficacy were four independent prognostic factors for PFS, while age, menopausal status, disease free interval, 4 subtypes, previous treatments, number of metastatic sites, SUVmax value and subsequent treatment efficacy were independent prognostic factors for OS. Conclusions: 18F-FDG uptake correlates with molecular subtypes in women with advanced breast cancer. Baseline SUVmax is an independent prognostic factor for survival of patients with advanced breast cancer, especially those with luminal subtypes.
Extracellular matrix and breast cancer cells' response to trastuzumab: The role of glycosaminoglycans, heparanases, and syndecan-1.
Authors: Pinhal Maria Aparecida Silva , Suarez Eloah Rabello , Nader Helena Bonciani , Del Giglio Auro
Published: March 2020

10568

Background: Trastuzumab is an antibody anti-epidermal growth factor 2 receptor (HER2), which improves disease-free and overall survival in HER2 positive breast cancer. Nevertheless, many patients become resistant to this treatment. Heparanase (HPSE) is an enzyme that is responsible for removal of heparan sulfate (HS) chains from proteoglycans, generating free oligosaccharides that modulate many physiopathological functions, including tumor developing. We have analyzed whether some extracellular matrix components influence trastuzumab efficacy. Methods: Heparanase-1 (HPSE-1) overexpression effect was analyzed using MCF7 cells stable transfected with HPSE-1 cDNA (MCF7-HPSE-1). HPSE-1, HPSE-2, Syndecan-1 (Syn-1) and HER2 expression, HPSE-1 activity and cell viability were evaluated in different breast cancer cells treated or not with trastuzumab. The glycosaminoglycans synthesis and shedding were also evaluated. Trastuzumab and HS binding were analyzed by confocal microscopy and Fluorescence Resonance Energy Transfer (FRET). Results: MCF7 transfected with HPSE-1 cDNA becomes completely resistant to trastuzumab. HS affinity by Trastuzumab was then tested, showing that they bind in high levels and this binding is necessary to antibody activity. In MCF7 cells, trastuzumab decreases HPSE-1, HPSE-2, HER2 and Syn-1 mRNA expression, while in MCF7-HPSE-1 the antibody increases the expression of these molecules. Conclusions: Our results have demonstrated that an ideal concentration of HS in cell surface, regulated by trastuzumab, is necessary to its action, beyond HER2 high levels. High HS concentration at cell surface enhances the antibody amount disposable to interact with HER2 in cell surface, determining breast cancer cells susceptibility to trastuzumab. These new insights could be useful when devising strategies for overcoming trastuzumab resistance in HER2 positive cancers. Supported by FAPESP, CNPq, CAPES.
Accuracy of microRNA-based classification of metastases of unknown primary.
Authors: Pavlidis Nicholas , Pentheroudakis George E. , St. Cyr Brianna , Spector Yael , Meiri Eti , Fountzilas George , Gousia Anna , Benjamin Hila , Malamou-Mitsi Vassiliki , Kotoula Vassiliki , Stoyianni Aikaterini , Krikelis Dimitrios , Sanden Mats Olot , Ashkenazi Karin ,   Hellenic Cooperative Oncology Group
Published: March 2020

10575

Background: Identification of the tissue of origin of metastatic tumors is important for estimation of prognosis and patient management. Carcinoma of unknown primary (CUP) is not uncommon in oncology, representing 3-5% of all newly found malignancies. We used a microarray-based test that uses the expression of 64 microRNAs to retrospectively evaluate tumors from CUP patients. Methods: A cohort of resected metastatic lesions from patients diagnosed with CUP was studied blindly on the microRNA-based test. The cohort included 93 samples (from 92 patients) with tissue adequate for the test. Eight samples failed due to inadequate RNA quality; 85 samples (84 patients) were processed successfully. Test results were compared with clinical presentation including imaging, pathological data (histology and IHC) at initial CUP diagnosis and with clinical management and outcome data at the completion of each patient`s follow up. Results: The test results were fully concordant with the diagnosis based on all the clinical and pathological information available including follow-up and outcome in 92% of patients compared to ~70% agreement with the patients’ diagnosis at initial presentation, before additional data gathered throughout patient management. Two different metastases from the same patient yielded the same result. The microRNA test assigned a single tissue of origin for 51 patients and two tissues of origin in 33 patients, with the first being the more likely diagnosis. When comparing only the first (or single) diagnosis, a concordant level of 88% was achieved. Conclusions: In a retrospective, well studied cohort of metastases from CUP patients, a previously developed test based on the expression profile of 64 microRNAs allowed accurate identification of tissue of origin in 92% of the cases. This study validates the high accuracy of the test on real CUP patients. The high concordance of the test results to the final tissue of origin diagnosis of the patient, even in cases where the initial diagnosis at CUP presentation was discordant, demonstrates the importance of the test in yielding additional data valuable for patient management at an early stage of the patient’s treatment plan.
Defining a FISH chromosomal aneusomy panel for predicting lung cancer in the setting of CT-detected lung nodules.
Authors: Franklin Wilbur A. , Skokan Margaret , Lewis Marina T , Feser William , Wolf Holly J , Miller York E , Merrick Daniel , Barón Anna E , Varella-Garcia Marileila
Published: March 2020

10580

Background: Early detection of lung cancer by CT is supported by the National Lung Screening Trial; but while sensitivity of CT is high, specificity is low. Biomarkers to predict the malignant nature of CT detected lung nodules would have great clinical utility. We previously found in a nested case-control study that a 4-target chromosomal aneusomy (CA) FISH panel exhibited sensitivity/specificity of 76%/88% in sputum samples of heavy smokers obtained within 18 months of lung cancer diagnosis. We hypothesized that CA-FISH may be an effective biomarker to assist with clinical decisions in the setting of CT detected lung nodules of indeterminate etiology and attempted to identify a more effective reagent. Methods: Homebrew probes encompassing genomic sequences of EGFR, NXK2-1, PIK3CA, MYC, BRF2, SOX2, PPMID, FGFR1 and the commercial reagent LSI D5S721/D5S23 (Abbott Molecular) were combined in 2-4-target FISH assays to investigate tissue copy number in early stage lung squamous cell carcinoma (SCC, N=19) and adenocarcinoma (AC, N=20). Logistic regression models were used to estimate predictive discrimination [sensitivity, specificity, area under the ROC curve (AUC)]. Results: Copy number gain was largely detected for all markers (mean range 3.39 - PPMID to 4.67 - MYC). Mean copy number of PI3CA, BRF2, SOX2 and FGFR1 were significantly higher in SCC than AC, while NKX2 and MYC were marginally higher in AC than SCC. Gene amplification was detected for all 9 markers, most frequently for SOX2 and FGFR1 (6 and 5 cases) with significant overlap between FGFR1/BRF2 and SOX2/PIK3CA. Based on the AUC results and the existence of targeted inhibitors, the probe set EGFR/FGFR1/MYC/PIK3CA was selected as a candidate for further development as an adjunct to CT screening for early detection. For this selected set,the optimal cutoff based in the linear predictor from logistic regression yields a sensitivity and specificity of 0.85. Conclusions: A highly sensitive/specific CA-FISH probe set was identified which may well complement CT screening in the early diagnosis of lung cancer. This probe set will be tested in the setting of CT detected lung nodules. (Supported by LUNGevity and NCI-Lung Cancer SPORE grants).
89 Zr-bevacizumab PET imaging in metastatic renal cell carcinoma patients before and during antiangiogenic treatment.
Authors: Oosting Sjoukje , Brouwers Adrienne H. , Van Es Suzanne C. , Nagengast Wouter B. , Oude Munnink Thijs H. , Lub-de Hooge Marjolijn N. , Hollema Harry , De Jong Johan R , de Jong Igle J. , de Haas Sanne , Scherer Stefan , Sluiter Wim J. , Dierckx Rudi A , Bongaerts A. H.H. , Gietema Jourik A. , De Vries Elisabeth
Published: March 2020

10581

Background: Renal cell cancer (RCC) is characterized by high VEGF production leading to excessive angiogenesis. To visualize VEGF, we performed serial 89Zr-bevacizumab-PET scans before and during antiangiogenic treatment in RCC patients. Methods: Metastatic (m) RCC patients who received sunitinib (50 mg once daily, 4 out of 6 weeks) or bevacizumab (10 mg/kg every 2 weeks) plus interferon (IFN 3-9 MU 3x/week), underwent 89Zr-bevacizumab-PET scans at baseline and after 2 and 6 weeks, and CT scans at baseline and every 3 months. Tracer uptake in tumor lesions was quantified with maximum Standardized Uptake Value (SUVmax). Relationship between baseline and Δ SUVmax and time to progression (TTP) was analyzed. Wilcoxon test was used to compare scans, Kaplan-Meier method for survival analysis. Results: 22 out of 26 patients were evaluable, 11 per treatment. On 89Zr-bevacizumab-PET, 131 out of 231 lesions ≥ 10 mm (detection limit) were visible and 125 quantifiable. Mean SUVmax at baseline was 10.1 (SD 8.4; range 2.3 - 46.9). During bevacizumab/IFN treatment, SUVmax consistently decreased (mean decrease 47.0% 95% CI 39.1-54.9, P<0.0001) at 2 weeks with a further decrease of 9.7% (95% CI 0.86-18.5, P=0.016) at 6 weeks. After 2 weeks sunitinib, there was only a modest decrease in mean  SUVmax  (14.6%, 95% CI 1.57-27.63, P=0.0064) with a wide range (-80.4% to +269.9%) and an overshoot of 84.4% (95% CI 47.8-120.9, P=0.0001) after 2 drug free weeks. TTP was longer in (n=15) patients with baseline SUVmax > 11.1 (highest normal tissue uptake) in the 3 most intense lesions than in those with a lower value (median 89.7 vs 22.8 weeks, HR 0.16, 95% CI 0.04 - 0.70). TTP was longer in patients (n=11) with an absolute Δ SUVmax >6.00 in the most intense lesion at 2 weeks (HR 0.25, 95% CI 0.06-0.98). Conclusions: 89Zr-bevacizumab-PET visualizes tumor lesions in mRCC patients. Different changes in tumor tracer uptake after start of bevacizumab/IFN versus sunitinib indicate that these drugs induce different angiogenic responses. High baseline SUVmax and large change in SUVmax corresponded with longer TTP, suggesting that 89Zr-bevacizumab-PET may help to identify patients who benefit the most from antiangiogenic treatment.
Serum HER2 in the context of circulating tumor cells in patients with metastatic breast cancer.
Authors: Mueller Volkmar , Riethdorf Sabine , Rack Brigitte Kathrin , Janni Wolfgang , Fasching Peter A. , Solomayer Erich , Aktas Bahriye , Kasimir-Bauer Sabine , Pantel Klaus , Fehm Tanja N. ,   on behalf of the DETECT Study Group
Published: March 2020

10599

Background: Circulating tumor cells (CTC) reflect an aggressive tumor behavior by hematogenous tumor cell dissemination. Overexpression of HER2 in breast cancer (BC) is associated with increased angiogenesis and therefore potentially linked to increased hematogenous tumor cell spread. The aim of the analysis was to investigate whether concentrations of serum HER2 (sHER2) deliver prognostic information in the context of CTC detection in metastatic BC patients. Methods: Blood was obtained in a prospective multicenter setting from 254 patients with metastatic BC at the time of disease progression. sHER2 was determined using a commercial ELISA-kit (Wilex). CTC were detected with the CellSearch system (Veridex). Patients received systemic treatment according to national and international guidelines including HER2-targeted treatment. Results: Five or more CTC were detected in 122 of 245 evaluable patients (49.8%).119 of 251 (47%) metastatic patients had serum sHER2 levels above 15ng/mL. Median PFS was 9.2 months (95%-CI: 9.9 – 13.0 mths) with elevated sHER2 versus 11.4 mths (9.9 – 13.0 mths) with non-elevated levels (p=0.07). OS was 17.4 mths (14.6 – 20.3 mths) vs. 26.5 mths (23.1-29.8 mths; p<0.01). In patients with 5 or more CTC, serum levels were above the cut-off for sHER2 in 61% vs. 33% in those with less than 5 CTC (p< 0.01). Patients with elevated sHER and 5 or more CTC hat a PFS of 9.1 mths (7.2 – 11.1 mths) and a OS of 14.5 mths (11.8 – 17.2 mths), those with non-elevated sHER2 and less than 5 CTC a PFS of 12.1 (10.1 – 14.1 mths) and a OS of 29.5 month (25.4 – 33.6 mths) (p=0.15 for PFS and p< 0.01 for OS). Including sHER2, CTC and established prognostic factors in the multivariate analysis, the presence of CTC, line of therapy, ER and HER2 status of the primary tumor remained independent predictors of OS. Conclusions: Elevated serum levels of sHER2 are associated with the presence of CTC and indicate poor clinical outcome. However, sHER2 has no independent prognostic value when presence of CTC were taken into account.
Isolation and expansion of circulating tumor cells (CTC) from melanoma patients using a novel cell culture technique.
Authors: McGregor John R. , Samlowski Wolfram E. , Tharkar Shweta , Donepudi Sreekanth , Ferrone Soldano
Published: March 2020

10614

Background: Identification of rare (>2-5) circulating tumor cells (CTC) in 7.5 ml blood by immunofluorescence assay (IFA) correlates with a poor prognosis in colon, breast, prostate and lung cancer. Changes in CTC count during treatment also predict the eventual patient progression and survival in these cancers. Existing assays do not detect melanoma CTC, however. In addition, isolation of viable CTC remains problematic. To overcome these limitations we attempted to develop novel melanoma CTC assays, using IFA and cell culture approaches. Methods: Blood samples were obtained from patients and controls following informed consent. The buffy coat (white cells + tumor) was isolated by Ficoll/Hypaque centrifugation, and split into 6 replicate cultures in proprietary TrueCells medium. After 21 days in culture, tumor colonies were counted, and stained for melanoma and leukocyte markers. Buffy coat cells from parallel blood samples were stained with a panel of CSPG4-specific mAb (a pan-melanoma marker) on ultraclean glass slides for analysis by immunofluorescence microscopy. Results: Blood samples were obtained from 16 melanoma patients, ages 28-87. Eight patients were men and 8 were women. CSPG4+ events (>2) were detected in 8/16 patients by IFA (range 0-52). In contrast, tumor cell colonies of >50 cells grew in 12 out of 16 patients with Stage 3 or 4 melanoma (range 0-1054), shown in Table. Cells isolated from CTC colonies produced melanin, stained for CSPG4 and other melanoma markers, but not for leukocyte markers. Control cultures grew no tumor colonies. Conclusions: Our pilot study shows that melanoma CTC can be identified by both IFA and cultured from blood in many patients with stage 3 or 4 melanoma. These CTC exhibited cytologic characteristics diagnostic of melanoma. The culture assay may represent a useful means of enumerating, isolating, and expanding viable melanoma CTC for further molecular study. [Table: see text]
Phase II trial of sorafenib (S) and vinorelbine (V) in metastatic breast cancer (mBC) with pharmacokinetics (PK) analysis.
Authors: Ferrario Cristiano , Miller Wilson H. , Charamis Helen , Langleben Adrian , Batist Gerald , Scarpi Emanuela , Nanni Oriana , Panasci Lawrence C.
Published: March 2020

1099

Background: S inhibits pathways involved in cancer resistance to treatments (Raf, VEGFR, PDGFR). This phase 2 trial aimed to define tolerability and efficacy of full doses of S and V in mBC. Toxicity data were previously reported: frequent dose reductions were noted, for which we investigated a possible PK interaction. Indeed, the metabolism of both S and V depends on hepatic CYP3A isoenzymes. Methods: Patients with measurable (RECIST), HER2 negative mBC received first-line therapy with V (30 mg/m2 days 1, 8 every 21) + S (400 mg bid). After 8 cycles patients could be switched to S alone. For PK analysis 6 patients started S on day 4 of cycle 1, to compare plasma levels of V, S and M2 (N-oxide active metabolite of S) when V and S were administered apart from each other versus concomitantly. Plasma samples were collected at time 0 (oral intake of S or right before V infusion), at completion of V infusion and after 0.5, 1, 2.5, 5, 7, 24, 48 and 72 hours from time 0 (cycle 1 day 1 for V and day 21 for S+M2; cycle 2 day 1 for both). Samples were analyzed using validated LC-MS/MS assays. Results: 27 patients (median age 57, 35-71) received a median of 8 cycles (1-28), with one patient still on treatment. With repeated cycles 48% of patients required at least 1 dose reduction and 3 patients discontinued therapy for toxicity. 30% of patients had a partial response, 85% had clinical benefit (including stable disease ≥ 4 cycles). Median progression-free survival was 5.7 months (95% CI 4.4-7.6). Plasma levels of V were influenced by S, with a mean Cmax right after the infusion of 1301 ng/mL for V administered alone (cycle 1 day 1) versus 2039 ng/mL with concomitant S (cycle 2 day 1; paired t-test, p=0.004). Plasma levels of S and M2 showed a greater degree of interpatient variability, with no significant difference observed in the presence or absence of concomitant V. Conclusions: Combining S with V at full doses is feasible, but not devoid of toxicity. A PK interaction may contribute to the frequent dose reductions. A reasonable option in clinical practice is to start therapy at lower doses of both agents, with a gradual dose increase if well tolerated. Promising efficacy of this combination is documented, with a very high rate of disease control.
Prognostic impact of local therapy of the primary tumor in metastatic breast cancer.
Authors: Himsl Isabelle Katrin , Ditsch Nina , Lenhard Miriam Susanne , Engel Jutta , Untch Michael , Bauerfeind Ingo , Friese Klaus , Harbeck Nadia , Kahlert Steffen
Published: March 2020

1114

Background: MBC is an incurable disease and the treatment aims are palliative. It is not known whether the difference in OS is the result of a selection bias or caused by dissemination of tumor stem cells in pat. without surgery. Methods: To identify the impact of surgical therapy of the primary tumor, a mono-institutional retrospective review from 1990-2006 was done in primary MBC pts. Results: We identified 269 pts. with primary MBC, 63 of whom had received no surgical local treatment. Mean follow up is 65 m for pts., observed mortality 87%. Location of metastases were bone only (36%), visceral or soft tissue (one organ only, 19%), multiple organs (40%) and including CNS metastases (5%). 50% had G3 tumors, 25% negative receptor status, 7% non-resectable local disease and 57% symptomatic metastases. In univariate analysis, pat. without local treatment had a median OS of 14.4m, pts. with local therapy 28.1m (p<0.001). Pts. not receiving local treatment were significantly more likely to have multiorgan or CNS involvement (p< 0.001), symptoms at diagnosis (p=0.009), non-resectable tumor (p<0.001) and were more likely to die within the first 30d after diagnosis (p< 0.001). In multivariate analysis, local treatment had no significant impact on OS. The only significant variables were: number of involved organs, symptoms at diagnosis, receptor status, grading, and size of the local tumor. The effect of local treatment on OS was not homogenous across subgroups. Local treatment was a significant factor in tumors with only one involved organ or asymptomatic disease. In all other groups, local treatment did not result in an OS benefit. Conclusions: Our cohort showed significantly improved OS in univariate analysis if the breast primary tumor had been removed in metastatic disease. Yet, the decision for local treatment was biased by the extent and presentation of metastatic disease. Pts. with more advanced MBC seem not to benefit from removal of the primary tumor. However, we see significant influence in pts. with limited and asymptomatic MBC. The potential dissemination of tumor stem cells from the breast primary in metastatic but locally untreated disease may only influence prognosis in pts. with limited disease.
Patient factors and satisfaction in the choice of contralateral prophylactic mastectomy.
Authors: Arrington Amanda Kathleen , London Karin , Chen Steven L. , Vito Courtney , Yim John H , Nelson Rebecca A. , Kruper Laura
Published: March 2020

1117

Background: The percentage of women undergoing contralateral prophylactic mastectomy (CPM) has more than doubled in recent years. The underlying reasons patients choose CPM have not been fully evaluated. Our objective was to survey patients who have undergone a unilateral mastectomy with or without CPM to identify reasons surrounding their decisions. Methods: After obtaining IRB approval, a 30-question cross-sectional validated survey was mailed to 691 patients who underwent mastectomy from 1972 to 2011 and are receiving treatment or surveillance at City of Hope. The questionnaire queried the factors behind the choice of surgery for each patient. Demographic questions were included and patient charts were also reviewed. Results: The overall response rate was 53% (N=368). Patients were classified into those who underwent mastectomy with CPM (N=139, 38%) and those who underwent mastectomy without CPM (no-CPM) (N=229, 62%). Of returned surveys, the median age was 50; 24% of patients reported a family history of breast cancer (42% CPM vs. 13% no-CPM, p<0.0001) and 80% of patients had education beyond the high school level (87% CPM vs. 77% no-CPM, p=0.013). PM patients reported being “very concerned” about breast cancer more often than no-CPM patients (46% vs. 34%, p=0.033).The primary reasons for CPM were: concern of recurrence (55%), cosmetic symmetry (27%), physician recommendation (17%), and unclear pre-operative imaging (9%). When questioned about regrets, the top response was decreased sensation (26%). Although 81% of CPM patients were “very satisfied” with their decision, 32% of no-CPM patients reported the same level of satisfaction with their decision (p<0.0001). For no-CPM patients, the primary reasons for the choice of no-CPM was physician advice and “monitoring is sufficient”; with 18% of the responders still considering a CPM. Conclusions: Patients’ perceived risk of contralateral breast cancer is the primary reason for CPM. CPM patients tend to be more satisfied with their decision compared to no-CPM patients. This may be related to the active decision-making thought processes and education necessary to choose CPM. Further patient education is warranted to minimize the risk of regret in making this decision.
Feasibility of sentinel node biopsy in patients with locally advanced breast cancer after neoadjuvant therapy: A pilot study.
Authors: Tibau Martorell Ariadna , Duch Joan , Quintana Maria Jesus , Lopez Vilaro Laura , Ojeda Belen , Alonso M Carmen , Ramon y Cajal Teresa , Lerma Enrique , Moral Antonio , Capdevila Enric , Pineda Rosa , Sabate Josep Maria , Estorch Montserrat , Barnadas Agust
Published: March 2020

1120

Background: Sentinel lymph node biopsy (SLNB) is a widely used staging method for patients with early breast cancer. Neoadjuvant Therapy (NT) modifies the anatomical conditions in the breast and axilla, and thus reliability of SLNB after NT remains controversial. The aim of this study is to prospectively evaluate the feasibility and accuracy of this procedure in this particular group of patients. Methods: Between December 2007-2011, 69 patients (mean age 56 years) with locally advanced breast cancer (LABC) were prospectively studied. Patients were T1-4, N0-1, M0. Prior to surgery, 61 patients received chemotherapy (CT) (adryamicin/cyclophosphamide followed by docetaxel) and 8 patients endocrine therapy (ET). Thirty nine patients were initially node-negative (cN0) and 30 patients had clinical/ultrasound node-positive confirmed by cytology (cN1) at presentation. All patients were clinical and ultrasound node-negative after NT. The study contained two groups of patients: group A (validation) included the first 29, associated with an axillary lymph node dissection (ALND) after NT, in order to validate the study, and group B included the last 40, only associated with an ALND when SLNB was positive or not found. Results: Whole SLNB identification rate was 89.9%, and no significant differences were found between patients initially cN0 (92%; 36/39) and initially cN1 (87%; 26/30). Four of 7 patients in whom SLNB was not found had residual nodal metastasis after NT (3 of them were initially cN1). Sentinel lymph nodes were successfully identified in 87% (7/8) of patients after ET and in 90% (55/61) of patients after CT. There was one false negative (FN) case after CT in group A (9% of overall false negative rate, initially cN0) and there were no FN cases after ET. Positive SLNB were higher in initially cN1 group (53%; 16/30) than in initially cN0 group (18%; 7/39). Conclusions: SLNB after NT (CT or ET) is safe and feasible in patients with LABC, not only in initially cN0 but also in initially cN1. It accurately predicts the status of the axilla and avoids unnecessary ALND.
Association of pathologic complete response following neoadjuvant chemotherapy with survival among young women with breast cancer.
Authors: Greenup Rachel Adams , Bardia Aditya , Buckley Julliette M , Niemierko Andrzej , Camp Melissa , Coopey Suzanne , Gadd Michele , Schapira Lidia , Taghian Alphonse G. , Smith Barbara L. , Specht Michelle Connolly
Published: March 2020

1122

Background: Neoadjuvant chemotherapy is increasingly being used in the treatment of breast cancer, yet data on efficacy and significance of pathologic complete response (pCR) is limited among young women. We sought to determine whether timing of chemotherapy impacted disease-free (DFS) or overall survival (OS), and whether pCR is associated with improved prognosis among young women with breast cancer. Methods: We performed an IRB-approved review of women ≤40 years old who received treatment for stage I-III breast cancer during 1996-2008 at our institution. DFS and OS were determined through use of state tumor registry, death certificate data, and Social Security Master Death Index. Tumor biology was categorized as hormone receptor positive (HR+), HER-2+, or triple negative (TN) breast cancer. pCR was defined as lack of invasive cancer in the breast and axilla on final pathologic review. Cox regression analyses were conducted to evaluate the hazard ratios (HRs) of the association between chemotherapy and outcomes. Results: 370 women ≤40 years old (median age = 36.5, range: 22-40) were treated with systemic therapy for stage I-III breast cancer. 54.7% of tumors were HR+, 20.9% were HER-2+, and 24.4% were TN. After adjusting for stage, there was no difference in DFS or OS among women who received neoadjuvant versus adjuvant chemotherapy (p=0.6 and 0.5 respectively). pCR following neoadjuvant chemotherapy was higher among HER-2+ (50%) and TN (28.6%) tumors when compared to HR+ tumors (17.6%). Among women who received neoadjuvant chemotherapy, 10-year DFS and OS rates were significantly higher when pCR was achieved when compared to lack of pCR (HR=0.20, p value=0.01 and HR=0.13, p=0.05). pCR with neoadjuvant chemotherapy trended towards higher 10-year DFS and OS when compared to women who received adjuvant chemotherapy (HR=0.30, p value=0.08 and HR=0.20, p=0.1). Conclusions: pCR after neo-adjuvant chemotherapy is associated with improved disease-free and overall survival in young women with breast cancer. Pathologic complete response may be a valuable surrogate marker for survival, and aid in the evaluation of therapeutic efficacy in young breast cancer patients.
Breast cancer surgery during pregnancy.
Authors: Surapaneni Rakesh , Jozefara Jolanta , Hendershott Karen , Hunter Krystal , Cardonick Elyce
Published: March 2020

1127

Background: There is limited literature on breast surgery during pregnancy. We present prospective registry data on 88 breast cancer patients who underwent breast cancer surgery during pregnancy. Methods: The Cancer and Pregnancy Registry is a voluntary international registry that prospectively collects the clinical course, treatment, and disease outcome of women diagnosed with cancer during pregnancy and the perinatal and neonatal outcomes of their children. Results: We identified 88 patients who were diagnosed with breast cancer and had surgery while pregnant. 59 patients (67%) underwent Mastectomy while29 patients (32%) underwent breast conserving surgery (BCS). Out of 43 patients who underwent BCS as their first surgery 13 patients (30.23%) required subsequent mastectomy during pregnancy. 15 patients (34.88%) from the BCS group and 4 patients (8.69%) from the Mastectomy group had positive margins. There was no significant difference between patients who underwent mastectomy vs BCS based on Age (34.67 vs 34.72 P: 0.97), gestational age at surgery (14.05 vs 16.06 P: 0.23) or ER positivity (47.5% vs 46.4% P: 0.93). 2 patients had neo-adjuvant chemotherapy. 17 patients (19.31%) had sentinel lymph node biopsy. 37 patients (42%) had a pregnancy complication. There was no difference in the rate of complication based on mastectomy vs BCS(45.8% vs 34.5% P: 0.31). There was only 1 patient (from mastectomy group) that delivered within 2 weeks of surgery. Of the 17 patients (19.3%) with spontaneous preterm delivery, there was no difference between Mastectomy and BCS group (22% vs 13.2% P: 0.41). Of the 25 patients (28.4%) with birth complications, there was no significant difference between mastectomy vs BCS (30.5% vs 24.1% P: 0.53). There was also no difference in mean birth weight between the groups (2598 grams vs 2672.3 grams P: 0.57). Conclusions: The data supports the safety of breast cancer surgery during pregnancy. In addition, there were no identified adverse effects in patients who underwent BCS as opposed to mastectomy. Of note, only 19% of patients underwent sentinel node biopsy which is considered the standard of care in early breast cancer patients regardless of pregnancy status.
Dexrazoxane exposure and risk of secondary acute myeloid leukemia in pediatric cancer patients.
Authors: Walker Dana Marie , Li Yimei , Huang Yuan-Shung , Seif Alix Eden , Kavcic Marko , Torp Kari , Fisher Brian , Aplenc Richard
Published: March 2020

1504

Background: Dexrazoxane (DXZ) is an effective cardioprotectant in children with leukemia and solid tumors. However, the potential risk of secondary acute myeloid leukemia (AML) limits DXZ use. We compared the incidence of secondary AML in pediatric cancer patients with and without DXZ exposure to estimate the risk of DXZ-associated secondary AML. Methods: We conducted a retrospective cohort study of anthracycline exposed pediatric cancer patients (excluding de novo AML) hospitalized from January 1999 to March 2011 in 43 freestanding children’s hospitals in the Pediatric Health Information System (PHIS) database. Secondary AML was defined as an ICD9 code for AML that occurred at least 90 days after first anthracycline exposure. Proportions of patients with secondary AML were compared between patients with and without an exposure to DXZ after the initial anthracycline exposure. Results: During the study period of interest, 15,532 pediatric cancer patients were exposed to anthracycline, of which 1404 (9.04%) subsequently received DXZ. Secondary AML was identified in 235 (1.51%) patients. Patients ≥ 10 years of age, black patients, patients in New England and the Midatlantic regions, and those with bone tumors were significantly more likely to have received DXZ. The unadjusted incidence of secondary AML in the DXZ exposed and unexposed patients did not differ significantly (1.21% v. 1.54%, p=0.3308). After adjusting for these variations in demographics, the incidence of secondary AML still did not significantly differ between DXZ exposed and unexposed patients (p=0.6224). Conclusions: Our findings suggest that DXZ exposure does not lead to an increased risk of secondary AML in children. These data are important given the conflicting results from individual clinical trials about the risk of DXZ-associated secondary AML. While subject to well-known limitations of administrative database analyses, these data represent the largest cohort of DXZ exposed patients with available data on the occurrence of secondary AML. Additional multivariate analyses of chemotherapeutic covariates and time to secondary AML are ongoing.
Sensitivity of clinical BRCA1 testing compared with linkage analysis.
Authors: Shah Payal D. , Garber Judy Ellen , Stopfer Jill , Powers Jacquelyn , Nathanson Katherine L. , Domchek Susan M.
Published: March 2020

1506

Background: Specific clinical interventions in BRCA mutation carriers reduces the risk of breast and ovarian cancers and may improve survival; thus,identification of mutation carriers is important. The sensitivity of current BRCA mutation testing is unclear as a “gold standard” test is lacking. We assessed the BRCA1 mutation detection rate with current comprehensive clinical testing using linkage analysis as the comparator. Methods: 26 families with linkage analyses results available were included in this analysis. BRCAPRO, BOADICEA, and other risk estimation models were applied. Maximum-likelihood linkage analyses were performed to compute two-point and multipoint LOD scores using previously described BRCA1 –linked genetic markers; scores were classified as linked, not linked, or suggestive. At least one individual from each family underwent comprehensive testing. Results: Of 26 families analyzed, 9 demonstrated linkage and 4 demonstrated suggestive linkage to BRCA1. Of these 13 families, 12 were found to have BRCA1 mutations: a detection rate of 92.3%. In 3 of these 12 families, genetic mutation testing performed prior to large genomic rearrangement (LGR) testing was negative, demonstrating an improved detection rate with LGR testing which in this series was 23%. The 12 families with higher LOD scores and positive mutation testing had high mean prior probabilities by all models. Families which were not linked and who tested negative for mutations had lower mean prior probabilities. In one family, disease demonstrated linkage with a two-point LOD score of 1.59 and multipoint LOD of 0.85 and all risk estimation models yielded high prior probabilities. Despite this, mutation testing was negative by full sequencing and MLPA analysis. Conclusions: When evaluated in a sample of families from high-risk clinics, current comprehensive testing compares well to linkage data. The inclusion of LGR testing has improved the mutation detection capability of clinical testing; however, some mutations may still be missed. Negative mutation testing results should be interpreted in the context of family history and prior probability during counseling. Despite recent advances, further improvements in genetic testing are warranted.
Use of PTEN protein dosage to predict for underlying germ-line PTEN mutations among patients presenting with thyroid cancer and Cowden-like phenotypes.
Authors: Ngeow Joanne Y. Y. , He Xin , Mester Jessica , Radhakrishnan Deepa , Lei Junying , Romigh Todd , Milas Mira , Eng Charis
Published: March 2020

1508

Background: Thyroid cancer is a major component of Cowden Syndrome (CS), a heritable syndrome characterized also by breast, uterine and kidney cancers. CS patients with an underlying germline PTEN mutation have a 70-fold increased risk of developing epithelial thyroid cancer. In contrast, <1% of sporadic epithelial thyroid cancer harbor a germline PTEN mutation. Thus, cost-efficient markers capable of shortlisting thyroid cancers for CS genetic testing would be clinically useful. Here, we analyzed the relationship of patient PTEN protein levels in predicting the presence of germline PTEN mutations. Methods: We conducted a 5-year, multi-center prospective study of 2792 CS and CS-like patients, all of whom had comprehensive PTEN analysis done. Analysis of PTEN and downstream proteins by immunoblotting was performed on total protein lysates from patient-derived lymphoblast lines. We compared PTEN protein expression levels between patients with pathogenic PTEN mutations (PTENmut+), and those with variants of unknown significance (VUS) or wildtype PTEN. PTEN immunohistochemistry (IHC) was performed on available thyroid samples. Results: Of 2792 CS/CS-like patients, 722 had thyroid cancer. PTEN germline pathogenic mutations were present in 36/722 (5%) patients. PTENmut+ cases presented at an earlier age (35 vs 42 years; p=0.02). PTEN frameshift and truncation mutations accounted for 55% of mutations. 95% (19/20) of PTENmut+ patients had blood-PTEN protein levels in the lowest quartile as compared to 27% (90/330) of PTEN wildtype/PTEN VUS patients (p<0.001). Low blood-PTEN levels predicted for PTENmut+ cases with a 99.6 % NPV (95%CI 97.7- 99.9) and a positive test likelihood ratio of 3.5 (95%CI 2.8-4.3). Affected thyroid tissues (n=22) from PTENmut+ cases showed loss of PTEN protein by IHC, correlating with patient blood PTEN levels (r2=0.30, p=0.016). Conclusions: Our study shows that PTEN protein dosage could serve as a molecular correlate predicting for germline PTEN mutation in CS and CS-like presentations of thyroid cancer. The clinical utility of PTEN IHC in identifying thyroid cancer patients for germline PTEN testing should be further explored.
Meta-analysis of cancer risk among users of insulin glargine.
Authors: Koechlin Alice , Boniol Mathieu , Robertson Chris , Bolli Geremia , Rosenstock Julio , Boyle Peter
Published: March 2020

1510

Background: The association between diabetes, its risk factors and treatments, and cancer risk and death is now high on the clinical and research agenda. Methods: All data regarding cancer risk and use of insulin glargine has been assembled and meta-analyses performed using state-of-the-art statistical methodology. Glargine is the most studied insulin in this regard. A random effects model was employed with tests for heterogeneity (I2) and publication bias. These meta-analyses are based on reports from epidemiological studies involving a total of 907,008 diabetic subjects and 2,597,602 person-years of observation. Results: Based on independent estimates from 14 studies, the Summary Relative Risk (SRR) for all forms of cancer was (SRR=0.90, 95% CI (0.82, 0.98)) and for breast cancer SRR=1.14 (95% CI (1.00, 1.29)). For new users of glargine, from 7 studies, the SRR for breast cancer was SRR=1.20 (95% CI (0.90, 1.58)). Based on independent estimates for 9 studies, for colorectal cancer the SRR was 0.73 (95% CI (0.59, 0.91)) and for prostate cancer SRR=1.16 (95% CI (1.03, 1.30)). Overall, the risk of developing cancer among users of insulin glargine is reduced compared to the risk of users of other insulins. Similarly, the risk of colorectal cancer is reduced among users of glargine. While above unity, the risks of breast cancer and prostate cancer are increased marginally. Potential limitations to this meta-analysis include that the comparison group was not the same in all studies but this could also be seen as a strength. This is not likely to invalidate the findings of this analysis nor would the fact that different adjustments were made in the individual studies. Conclusions: The current evidence gives no support to the hypothesis that insulin glargine is associated with an increased risk of cancer as compared to other insulins and should give reassurance to physicians and their patients. Given the short exposure time possible to glargine (less than 5 years maximum), it is not biologically plausible to have a causal link to common forms of cancer.
Next-generation sequencing to identify candidate gene for hereditary mixed polyposis syndrome.
Authors: Gornick Michele Caroline , Li Jun , Xu Jishu , Gruber Stephen B.
Published: March 2020

1515

Background: Rare monogenic disorders are often due to mutations that are highly penetrant, extremely rare, and strongly disrupt normal biology. Hereditary mixed polyposis syndrome (HMPS, OMIM ID %601228), is characterized by a mixture of atypical juvenile polyps, hyperplasic polyps, sessile serrated adenomas and an increased risk of colorectal cancer. Polyps appear to be inherited in an autosomal dominant fashion. The putative susceptibility locus initially mapped to 15q13-14, however, the genetic basis of this syndrome is not well understood, and no mutation or associated variants have been identified. Methods: Germline DNA from four individuals from a family with clinically and pathologically confirmed HMPS was subjected to massively parallel sequencing (Illumina GAII). Affected individuals had an average of 30x coverage of their exome and 10x coverage of their genome. Sequence calls were filtered using the criteria of ≥ 4x coverage, quality score over depth ≤ 50, depth of coverage ≤ 360, allele balance ≤ 0.75, number or MAPQ zero reads at locus < 4. Common variants were filtered out by excluding variants found in dbSNP (build131), 1000 Genomes Project, the Exome Variant Server or 80 unaffected controls sequenced by hybrid capture and whole exome sequencing. Polyphen2 and SIFT were used to predict pathogenicity of the novel, shared variants, and validated by Sanger sequencing. Expression levels of novel variants were examined in available tumor samples using qRT-PCR. Results: From the 32 previously unidentified nonsense, missense or splice site variants shared by the family members whose whole genomes were sequenced, only 5 (4 missense, 1 nonsense) were predicted to be damaging, leading to a small subset of novel candidate genes including ZNF426, which may be responsible for HMPS within this family. Conclusions: HMPS extremely difficult to accurately diagnosis and the genetic basis is unknown. Using next-generation sequencing we were able to detect previously unidentified low frequency allelic variants including a novel candidate locus.