bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of androgen receptors expression in triple negative breast cancer patients and its correlation with clinicopathological criteria: Our institutes experience.
Authors: Farag Kamel , Elfarargy Ola , El Shorbagy Shereen , Ahmed Safa , Harb Ola , Amin Reham , Gertallah Loay , Megahed Ola , Abdel-latif Rasha
Published: September 2018

e12584

Background: Triple negative breast cancer (TNBC) is a term that has been applied to breast cancers which lack expression of three receptors: estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2). It represents about 20% of breast cancers diagnosed worldwide. TNBC is a challenging type by its presentation criteria and limited options of treatment. Continuous research for finding specific target is the aim of scientists. Androgen receptors (AR) expression take special attention in this type of breast cancer as its expression can help for finding special targeted treatment as antiandrogen therapy.Purpose:is to assess the AR expression in TNBC patients and to correlate its expression with clinicopathological parameters and disease outcome of patients in study populations. Methods: This prospective study included 90 female patients confirmed as TNBC patients in medical oncology and clinical oncology departments, in Mansoura University and Zagazig University, Egypt, between December, 2013 to May, 2016. AR positive expression was defined as ≥10% nuclear immunostaining. Results: AR expression was positive in twenty seven (27/90) patients (30% ), and lack of its expression was significantly associated with younger age group(p < 0.001), higher grade(p = 0.017)& higher tumor stage(p < 0.001), presence of lymph node metastasis(p < 0.001) & distant metastases(p = 0.032), vascular(p = 0.044)& perineural invasion and high baseline CA 15-3 level (p < 0.001).Median follow up duration was 17.5months (range 6-40), 32/90 died (35.6%).Mean OS was 28months for AR negative TNBC patients versus 32months for AR positive patients. Twenty four of died patients (24/32) were AR negative. Three years OS was 50.8% and 44.1% for AR positive and AR negative respectively, but with nonsignificant P-value. Conclusions: Our study confirmed that AR positive expression in TNBC is a good prognostic feature and it can be sued as target for antiandrogen therapy in this group who is lacking any targettreatment.
Expression of androgen receptor and epidermal growth factor receptor in invasive breast cancer: A retrospective study of 1,438 patients from China.
Authors: Chen Junqing , Chen Zhanhong , Wang Xiaojia
Published: September 2018

e12587

Background: Triple-negative breast cancer (TNBC) is lack of clinically efficient targeted therapies and usually more aggressive with higher rate of distant metastasis and poor overall survival as compared with other breast cancer subtypes. Recent evidence demonstrates that androgen receptor (AR) and epidermal growth factor receptor (EGFR) are involved in the pathogenesis of TNBC. The aim of this study was to explore the expression of AR and EGFR in invasive breast cancer and evaluate the potential of AR and EGFR as biomarkers in TNBC. Methods: In this retrospective study, we analyzed 1438 patients with invasive breast cancer in our hospital from 2015 to 2016. Estrogen receptor (ER) expression, progesterone receptor (PR) expression, Ki-67 index, AR and EGFR expression were detected by immunohistochemical assay. HER2 state was determined by immunohistochemical and FISH assay. χ2 test was used for the analysis. Results: Among 1438 breast cancer patients, 272 (18.9%) cases were TNBC and 1165 (81.0%) cases were non-TNBC. TNBC patients had a low AR expression as compared with non-TNBC patients (29.8% vs 90.2%). There was a significant difference in AR expression in TNBC compared in non-TNBC ( P= 0.000). In contrast, TNBC patients had a high EGFR expression as compared with non-TNBC patients (90.9% vs 21.1%) ( P= 0.000). There was also a significant difference in Ki-67 index in TNBC compared in non-TNBC (89.9% vs 70.1%) ( P= 0.000). AR-positive TNBC patients had a low Ki-67 index expression as compared to AR-negative TNBC (82.7% vs 93.6%). No significant difference of EGFR expression was found between AR-positive TNBC and AR-negative TNBC. Conclusions: AR expression is associated with Ki-67 index and may be as a potential biomarker for targeted therapy in AR-positive TNBC patients.
The association between neutrophil to lymphocyte ratio and overall survival in patients with triple-negative breast cancer.
Authors: Patel Dilan Anil , Hassan Bilal , Luo Jingqin , Ma Cynthia X. , Campian Jian Li
Published: September 2018

e12591

Background: Recent reports have suggested that an elevated neutrophil to lymphocyte ratio (NLR) is associated with poor outcomes in various malignancies. Furthermore, radiation therapy (RT) alone or in combination with chemotherapy often results in reduced absolute lymphocyte counts (ALC), which has been postulated to impair host immune surveillance and anti-tumor responses. We sought to better understand whether an elevated NLR results in impaired OS in patients with triple-negative breast cancer. Methods: Our retrospective analysis was performed on a database of patients with biopsy proven triple-negative breast cancer treated at Washington University in St. Louis between 2002 and 2010. Patients who received radiation therapy and had adequate follow up in terms of clinical documentations and laboratory data were included. NLR and ALC were collected at baseline, post-adjuvant chemotherapy, prior to RT, end of RT, 2 months post RT, 1 year post RT, and completion of all planned treatments. Results: Total of 155 patients were included. We used a cutoff value of 3.0 to classify high NLR. Wilcoxon rank-sum test was used to compare NLR at each time point between deceased and alive patients. High NLR post chemotherapy is associated with worse OS (HR 1.127, 95% CI = 1.016-1.249; p<0.05). In addition, NLRs from end of RT, 2 months post and 1 year post RT are associated with worse OS: (HR 1.109, 95% CI = 1.059–1.161; p < 0.001); (HR 1.074, 95% CI = 1.041–1.109; p < 0.001); (HR 1.069, 95% CI = 1.048–1.091; p < 0.001) respectively. Conclusions: High NLR post-chemotherapy and RT are associated with worse OS in patients with triple-negative breast cancer.Further studies are warranted to establish NLR as a prognostic marker and an addition to risk prediction models. [Table: see text]
BRCA mutation carriers undergoing combined mastectomy with immediate reconstruction and gynecologic risk-reducing surgery: An analysis of outcomes.
Authors: Ivanov Olga , Centers Nicole , Wiercinski Karen , Reina Eva , Buffington Cynthia , Caceres Aileen
Published: September 2018

e13004

Background: The aim of this study was to assess outcomes of a multidisciplinary model for combined prophylactic and/or therapeutic mastectomy with immediate reconstruction and gynecologic risk-reducing surgery in patients with hereditary breast cancer syndromes. Methods: Between 2012 and 2016, 12 patients with documented BRCA1 and BRCA2 mutations underwent combined surgery at our facility. Procedures included bilateral mastectomy, axillary lymph node staging, immediate expander based reconstruction and minimally invasive salpingo-oophorectomy with added hysterectomy when indicated. All procedures were performed in a single operating room setting by rotating subspecialty teams. Results: Patient characteristics included a mean (+SD) BMI of 32.1±6.7 (23-44) kg/m2 and ASA of 2.2±0.4 (2-3). Fifty-eight percent (7/12) were premenopausal. Patient’s average age was 45.8+10.8 (30-73). Therapeutic mastectomy for breast cancer was performed in 4/12 patients. Of the 4 affected patients 2 had neo-adjuvant chemotherapy for locally advanced cancer. The remaining 8/12 had prophylactic mastectomies. Risk-reducing salpingo-oophorectomy was performed in 12/12 patients. Seventy-five percent (9/12) underwent concurrent minimally invasive hysterectomy for suspected gynecologic malignancy, leiomyoma, complex endometrial hyperplasia, dysmenorrhea and menorrhagia. Two gynecologic specimens required mini-laparotomy for removal. Mean total operative time was 283.3±66.5 (206-447) minutes and estimated blood loss (EBL) was 209.2±139.2 (50-500) ml. Hospital length of stay (LOS) was 1.4±0.7 (1-3) days. There were no significant differences (p > 0.05) in operative time, EBL, or LOS in comparing therapeutic to prophylactic mastectomies. Follow-up revealed no postoperative wound infections. Conclusions: Combined mastectomy with immediate reconstruction and gynecologic risk reducing surgery had no untoward surgical complications with a zero postoperative wound infection rate. Although a small study population, results indicate this approach is a prudent and feasible multidisciplinary model that can be offered to BRCA mutation carriers.
Germline and somatic SNVS calling in NGS panel tumor samples: Approaches to optimize tumor only genomic analysis for cancer precision medicine.
Authors: Sun Ruobai , Cingolani Pablo , Pantazi Angeliki , Eifert Cheryl , Huang Xiu , Bjonnes Andrew , Lyle Stephen , Protopopov Alexei , Vuzman Dana
Published: September 2018

e13011

Background: Clinical NGS is often limited by tumor only profiling. Discrimination between somatic and likely germline mutations when calling from tumor patient samples is a critical step for clinical genotyping. Many algorithms have been developed for somatic single nucleotide variant (SNV) detection in matched tumor-normal whole genome and whole exome sequencing. Here, we demonstrate approaches of how a cost-effective large gene panel sequencing can be used to call somatic and germline SNVs for tumor only samples. Methods: Tumor, adjacent normal, and matched normal samples are collected from five patients. The somatic mutations were called with GATK Mutect2 in tumor only and adjacent normal. The germline mutations were called individually for all 15 samples with GATK Haplotype caller. To remove germline mutations from tumor only somatic calls, the filters ExAc pop freq, 1000G pop freq, COSMIC were applied on the tumor only somatic calls. PPV (Positive predictive value) for each filter was calculated by dividing the number of somatic mutations in the post-filtering mutation data by the total number of unfiltered mutations. TPR (True Positive Rate, representing sensitivity) was calculated by dividing the number of true somatic mutations in the tumor-only post-filter. Results: Compared with germline mutations called from matched normal, 70% germline mutations were called in RAWE somatic calls. A PPV of 0.71 and a TPR of 0.95 were optimally provided when the filter ExAc pop freq > 0.01 and COSMIC ( > 5 occurrence) applied. For germline mutations called in tumor samples, when compared with those in blood samples and in adjacent normal samples, PPV is 0.99 and TPR is 0.97. For somatic mutations called with tumor-adjacent normal pair mode in Mutect2, PPV is 0.5 and TPR is 0.99. Conclusions: Optimization of tools and parameters in NGS large panels could detect somatic and germline variants with high specificity, sensitivity and accuracy, without matched or adjacent normal. For the germline variants, when adjacent normal is available, it could replace matched normal with high accuracy.
Pan-cancer panel testing in individuals with abnormal immunohistochemistry (IHC) staining of the mismatch-repair (MMR) genes.
Authors: Pan Shujuan , Cox Hannah C , Brown Krystal , Willmott Jamie , Gorringe Heidi , Mundt Erin , Rosenthal Eric Thomas , Bowles Karla , Coffee Bradford , Mancini-Dinardo Debora
Published: September 2018

e13014

Background: IHC staining of the MMR genes is often used to screen for Lynch syndrome (LS) in patients with newly diagnosed colorectal cancer (CRC) and endometrial cancer (EC). Genetic testing of MMR genes guided by IHC has historically been used to confirm a diagnosis of LS. Given the known genetic heterogeneity of LS-related cancers, we assessed the extent to which IHC results reliably predicted findings with pan-cancer panel testing. Methods: We analyzed results from pan-cancer panel testing of 750 individuals with abnormal IHC results from 2013-2016. The panel included the MMR genes and other genes associated with CRC and/or other cancers. All clinical data, including IHC results, were obtained from provider-completed test request forms. Results: CRC (66.0%) was the most common cancer among tested individuals with abnormal IHC results, followed by EC (35.1%). 236 pathogenic variants (PVs) were identified in 228 (30.4%) individuals, 8 of whom carried two distinct mutations. Overall, 191 (80.9%) PVs occurred in MMR genes that were concordant with IHC results. The remaining 45 (19.1%) PVs were not predicted by IHC results, and included two PVs in MMR genes ( MSH6 PV with MLH1/PMS1 absent in IHC, MSH2 PV with PMS2 absent in IHC). The majority of PVs that were not predicted by IHC results occurred in non-MMR genes associated with CRC and EC (n=27, 60.0%; see Table). Conclusions: In this cohort, PVs were identified in 30% of individuals with abnormal IHC who were tested with a pan-cancer panel. Nearly 20% of PVs occurred in non-MMR genes that would be missed by MMR gene-specific testing based on IHC results. Collectively, this suggests pan-cancer panel testing may increase diagnostic yield among individuals with abnormal IHC. [Table: see text]
Association of breast cancer risk in women of African ancestry with genetic variants in the TET-related DNA demethylation pathway.
Authors: Lee Kris M. , Wang Shengfeng , Huo Dezheng , Ogundiran Temidayo O. , Ojengbede Oladosu , Zheng Wei , Nathanson Katherine L. , Nemesure Barbara , Ambs Stefan , Zheng Yonglan , Olopade Olufunmilayo I.
Published: September 2018

e13015

Background: Imbalance in DNA methylation/demethylation cycles due to mutations in TET1, TET2, TET3, and TDG has been implicated in the onset and progression of breast cancer. However, few studies have assessed the relationship between genetic variants in the TET-related DNA demethylation pathway and breast cancer risk, particularly among women of African ancestry. Methods: We investigated 4095 single-nucleotide polymorphisms (SNPs) in four TET-related DNA demethylation pathway genes in the ROOT consortium, which includes women of African ancestry, in 1657 cases [403 estrogen receptor-positive (ER+) and 374 ER-negative (ER-)] and 2029 controls. Pathway and gene-level analyses were conducted using the adaptive rank truncated product (ARTP) test for 925 SNPs that were not highly correlated (r2 < 0.8), and SNP-level analyses were conducted with logistic regression, which was used to estimate the odds ratio (OR) and 95 % confidence intervals (CI). Results: The Tet-related DNA demethylation pathway was significantly associated with ER-negative breast cancer (pathway level P = 0.049). Gene-level analyses showed that TET1 was the candidate gene responsible for the association at the pathway level ( P = 0.008). SNP TET1 rs10998376 (OR = 1.21, 95% CI = 1.02-1.42, Padj = 0.0032) was statistically significant even after gene-level correction for multiple comparisons, and was associated with increased risk. There were no SNPs in genes with P > 0.05 in the ARTP tests that were significant after Boferroni correction. Conclusions: In conclusion, specific TET-related DNA demethylation pathway genes may contribute to breast cancer risk, in particular, to risk of ER-negative tumors in women of African ancestry.
Do BRCA 1 mutations affect selected molecular variables in women with breast and ovarian cancer carrying cerebral metastases?
Authors: Markowska Janina , Markowska Anna , Szarszewska Monika , Sajdak Stefan , Knapp Pawel , Grybos Anna , Olejek Anita , Bednarek Wiesława , Marszalek Andrzej , Markwitz Ewa , Jach Robert , Tomczak Piotr , Chudecka-Glaz Anita Monika , Ramlau Rodryg , Filas Violetta , Grybos Marian , Stanislawiak-Rudowicz Joanna , Jaszczyńska-Nowinka Karolina , Adamska Krystyna
Published: September 2018

e13017

Background: Cerebral metastases develop in 10-30% of patients with breast cancer and in around 3.3 to 4% of patients with ovarian cancer. The present study evaluates the expression of ER alpha and beta receptors, PR, HER2 and markers associated with metastases: stromal cell-derived factor-1 (SDF1) and its receptor CXCR4, breast cancer metastasis suppressor (BRMS1), astrocyte elevated gene (AEG-1), depending on the status of BRCA1 protein in cancerous cells of the patients (somatic mutation). Methods: The material originated from 30 women with breast cancer and 22 patients with ovarian cancer in whom cerebral metastases were detected. The studies were conducted on paraffin block sections, the markers were detected using immunocytochemistry, employing specific antibodies. Results: In the breast cancer group, BRCA 1 protein expression was detected in 11 patients, absence of the protein in 19. No significant differences were disclosed in the grade of ER, PR, HER2, SDF1, CXCR4, BRMS1 or AG-1 expression which would be dependent on the status of BRCA1. Expression of the proteins failed to correlate with patients' age, clinical advancement at diagnosis, presence of metastases to lymph nodes. Patients with no PR expression significantly more frequently manifested high expression of CXCR4 (p = 0.0436). The ovarian cancer group included 7 patients with expression of BRCA1 protein, absence of such expression was recorded in 15 patients. No statistically significant differences were disclosed in the expression of the studied factors which would be related to the status of BRCA1 in cancer cells. Also, no differences were detected in the expression of the studied factors which would depend on the patient’s age, primary advancement of the disease or histological type of the cancer. Conclusions: Among numerous molecular factors examined in women with breast or ovarian cancer no statistically significant differences were detected which would depend on BRCA1 protein status in cancer cells. The absence of PR expression in women with breast cancer was associated with high expression of CXCR4, which might indicate that PR-negative women with breast cancer exhibit higher metastatic potential.
Minnesota healthcare providers’ breast cancer screening practices at the extremes of age.
Authors: Teoh Deanna Gek Koon , Vogel Rachel Isaksson , Allen Alicia , Blaes Anne Hudson , Mason Susan , Nagler Rebekah , Raymond Nancy , Talley Kristine , Wyman Jean
Published: September 2018

e13037

Background: Breast cancer screening guidelines disagree on the age to initiate and discontinue screening. We sought to determine the age at which Minnesota providers initiate and discontinue breast cancer screening. Methods: A cross-sectional online survey of Minnesota primary care providers was conducted in 2016. The survey queried providers’ breast screening practices for average-risk women. Data were summarized using descriptive statistics and comparisons by professional characteristics were conducted using Chi-squared tests. Results: There were 805 respondents (8% of 10,392 invitees), of which 456 (56.7%) provided primary care to women and were included in the analysis. 316 (72%) were women, 193 (44%) were physicians, 50 (11%) were physician assistants (PAs), and 197 (45%) were advanced practice nurses (APNs). 85% practiced in a community setting. 38% had practiced > 20 years, and 27% had practiced < 10 years. Among respondents, 67%, 77% and 72% recommended screening mammography for women age 40-44, 45-49 and 70+ years, respectively. Compared to male providers, female providers were more likely to screen women age 40-44 years (73% vs. 49%; p < 0.0001) and 45-49 years (81% vs. 66%; p = 0.002), but there was no difference by gender for patients age 70+ years (72% vs. 74%; p = 0.89). Respondents reporting specialized interest in women’s health were more likely to screen women age 40-44 years (73% vs. 61%; p = 0.006), 45-49 years (83% vs 72%; p = 0.007) and older than age 70 years (77% vs. 69%; p = 0.04). Physicians were less likely to screen women age 40-44 and 45-49 years (57% and 71%, respectively; p = 0.001) than PAs (72%, 78%) and APNs (74%, 83%), but APNs were less likely to screen women age 70+ years (65% vs. physicians 79% vs. PAs 76%; p = 0.006). Number of years in practice was not associated with a difference in age at initiation of screening, however, increasing number of years in practice was associated with screening women age 70+ years (p = 0.02). Conclusions: Although breast cancer screening practices for average risk women vary by healthcare provider characteristics, a majority of Minnesota primary care providers initiate breast cancer screening between ages 40-49 years, and continue screening women age 70 years and older.
Cost-effectiveness of surveillance and prevention strategies in BRCA 1/2 mutation carriers.
Authors: Yamauchi Hideko , Nakagawa Chizuko , Kobayashi Makoto , Kobayashi Yusuke , Mano Toshiki , Nakamura Seigo , Arai Masami
Published: September 2018

e13051

Background: Cost-effectiveness analysis is important in healthcare, especially in Japan, where preventive measures for carriers of BRCA 1/2 mutations are not covered by health insurance. Methods: We developed Markov models in a simulated cohort of women aged 35–70, and compared outcomes of surveillance with risk-reducing mastectomy at age 35 (RRM), risk-reducing salpingo-oophorectomy at age 45 (RRSO), and both (RRM&RRSO), with quality adjustment. We used breast and ovarian cancer incidence, and adverse event rates from previous studies, adjuvant chemotherapy and hormonal therapy rates from Hereditary Breast and Ovarian Cancer Registration 2015, mortality rates from the National Cancer Center Hospital, Japan Society of Clinical Oncology and Ministry of Health, Labour and Welfare, and direct costs in 2016 Japanese yen from St. Luke’s International Hospital and Keio University Hospital. We used preference ratings for both of mutation carriers and controls (without known high risk) from a published study to adjust survival for quality of life (QALYs). Discount rate was 2%. Results: Compared with surveillance, RRSO and RRM & RRSO were dominant (cost-saving and more effective) and RRM was cost effective for BRCA 1 mutation carriers. RRM and RRM & RRSO were dominant, and RRSO was cost effective for BRCA 2 mutation carriers. Among four strategies including surveillance, RRM & RRSO was the most cost effective for BRCA 1 mutation carriers and RRM was the most cost effective for BRCA 2 mutation carriers based on preference ratings of controls. Conclusions: With quality adjustment, all the preventive strategies (RRM, RRSO and RRM&RRSO) were cost effective for BRCA 1 and 2. Using QALYs from the control group, RRM & RRSO for BRCA 1 and RRM for BRCA 2 were the most cost effective. We will use this result to promote insurance coverage for BRCA mutations carriers in Japan.
Breast cancer incidence according to age, race, and hormone receptor subtype: A SEER database analysis.
Authors: Schwartz Theresa Lynn , Wirth Lorinette , Diggs Laurence , Hinyard Leslie J.
Published: September 2018

e13059

Background: While incidence rates of breast cancer have been shown to vary based on age and race, hormone receptor (HR) subtype is an important prognostic indicator and it is unclear to what extent HR subtype varies across age and race. Identifying breast cancer at an early stage, especially in the more aggressive subtypes, correlates with improved overall outcomes. In this study we sought to examine the distribution age, race, within HR subtype in women diagnosed with incident breast cancer. Methods: Data from the SEER registry, years 2010-2013, was queried to produce race stratified age distributions of incident cases of invasive female breast cancer according to HR subtype: Her2+/HR+ (n = 21288), Her2+/HR- (n = 9325), Her2-/HR+ (n = 153130), Her2-/HR- (n = 24455). Race was categorized as White, Black, and Other. Mantel-Haenszel Chi-Square (χ2MH) test was used to determine whether racial variations across the age categories (20-44 years, 45-64 years, and 65+ years) were the same across hormone receptor subtypes. Results: Across all HR subtypes and race categories, incident breast cancer burden was highest among women aged 45-64 years (p < 0.001). Age distribution differed significantly across HR subtypes (p < 0.001). Variations across age distributions and race differed by HR subtypes (p < 0.001). When the incident burden for younger Black women (aged ≤ 44 years) to Black women aged 45-64 years was compared to the same age categories for White women, it was found that variations across the racial and age groups were different across HR subtypes (p < 0.001). These results would suggest a significant three-way interaction between age, race, and HR subtype. Conclusions: There are significant differences in breast cancer incidence according to age, race, and HR subtype. Further investigation into a mortality effect is necessary to determine breast cancer screening strategies when these variables are taken into consideration.
Relationship between survival to breast cancer and level of HER2 expression by immunohistochemistry.
Authors: Provencher Louise , Diorio Caroline , Desbiens Christine , Poirier Brigitte , Poirier Eric , Boudreau Dominique , Doyle Catherine , Popa Ion , Gagné Isabelle , Hogue Jean-Charles , Lemieux Julie
Published: September 2018

e13078

Background: Central review of NSABP B-31 showed that some central-review HER2-negative patients benefited from trastuzumab, but survival according to different levels of HER2 expression by immunohistochemistry (IHC) is unknown. The aim of the present study was to examine the survival of trastuzumab-naïve patients with breast cancer according to the level of HER2 expression by IHC. Methods: This was a retrospective study of all women who were treated for an invasive breast cancer at the Centre des maladies du Sein Deschênes-Fabia (Quebec City, Province of Quebec, Canada) between July 1999 and December 2010. Patients were grouped according to the HER2 status by IHC of their primary cancer (0 vs. 1+ vs. 2+ vs. 3+). Survival was obtained from the death registry of the Ministry of Health. Follow-up was censored on December 31st, 2012. Results: During the study period, 2571 patients with invasive breast cancer, with available HER2 status by IHC and survival data, and naïve to anti-HER2 therapy were treated at our center. Both 5- and 9-year overall survival (OS) decreased with increasing HER2 expression by IHC (9-year OS: 0: 86.2% vs. 1+: 71.3% vs. 2+: 73.9% vs. 3+: 69.3%; unadjusted log-rank test: P < 0.0001; adjusted P = 0.04 for 3+). Both 5- and 9-year breast cancer-specific survival (BCSS) decreased with increasing HER2 expression by IHC (9-year BCSS: 0: 90.7% vs. 1+: 81.8% vs. 2+: 77.0% vs. 3+: 75.4%; unadjusted log-rank test: P < 0.0001; adjusted P = 0.04 for 3+). Conclusions: Survival among trastuzumab-naïve breast cancer patients seems to follow a continuum across HER2 expression by IHC.
Mammography use, incidence, and survival of primary breast lymphoma.
Authors: Khudayar Humnah , Fallah Jaleh , Souaid Roy , Olszewski Adam J.
Published: September 2018

e13087

Background: Breast lymphoma is rare and, unlike in carcinoma, surgery is not the primary treatment modality, so early detection may not contribute to survival. Caon et al. ( Clin Breast Cancer 2012) reported that 85% of aggressive lymphomas are diagnosed by a palpable mass, while 56% of indolent subtypes, by mammography. Our objective was to compare incidence, clinical features, and survival of breast lymphomas according to prevalence of screening mammography. Methods: From the United States SEER registry, we selected primary breast lymphomas diagnosed in 2000-2013 among women ≥40 years old, distinguishing DLBCL, marginal zone (MZL), follicular (FL), and other histologies. Mammography use in county of residence was expressed as % of women ≥40 years old with a mammogram in past 2 years, estimated from the National Cancer Institute’s small-area models. We calculated incidence rates (IR) for each county, and compared them in a Poisson model (with 95% confidence intervals, CI). Head and neck (H&N) lymphomas were used as sensitivity controls. Overall survival (OS, from diagnosis) was compared in a Cox model adjusting for age, race, and median income in the county. Results: We identified 1662 cases of breast lymphoma, with a median age of 69 years. The most common subtypes were DLBCL (39%), MZL (26%), and FL (16%). Stage distribution was: 1 in 62%, 2 in 17%, and 3 or 4 in 21%. Incidence of breast lymphoma increased by 24% for every 10% increase in mammography use (IR ratio, 1.24, 95%CI, 1.15-1.34, P<.0001). This relationship was absent for controls with H&N lymphoma (IR ratio, 1.02, 95%CI 0.97-1.07, P=.43). In breast lymphoma, there was no difference in histologies ( P=.19), stage ( P=.83), or OS by mammography prevalence (hazard ratio 1.01 for every 10% increase, 95%CI, 0.87-1.18, P=.87). OS at 5 years was 60% for DLBCL, 77% for MZL, and 84% for FL. Conclusions: Prevalent mammography use is associated with increased incidence of breast lymphoma, without evident change in stage distribution or survival. Further research will be needed to investigate responsible causal pathways, or potential overdiagnosis. [Table: see text]
Identifying patients according to breast cancer stage and ER/HER2 receptor status using claims data.
Authors: De Luise Cynthia , Beachler Daniel C , Yin Ruihua , Jemison Jamileh , Cochetti Philip T , Gangemi Kelsey , Lanes Stephan
Published: September 2018

e13096

Background: Safety analyses of targeted oncology therapies often require cancer stage and receptor status. Automated claims databases offer the largest populations to study rare outcomes, but lack these characteristics. We conducted a validation study of claims data using predictive models to identify two cohorts of women with early-stage and advanced-stage ER+/HER2- breast cancer (ESBC and ASBC, respectively). Methods: Retrospective cohort and validation study using electronic data linkage of a nationwide claims database (HealthCore Integrated Research Database – HIRD) and Anthem’s Cancer Care Quality program (CCQP). The CCQP served as a validation sample. We used claims data to develop two predictive models to estimate breast cancer stage and receptor status. We applied these models to the HIRD to identify ER+/HER2- ESBC and ASBC cohorts. In each cohort we assessed adverse event (AE) rates. Results:: In addition to breast cancer diagnoses, predictive models for ER+/HER2- ESBC and ASBC included 21 and 15 factors, respectively (Table).When compared to an a priori ASBC algorithm developed from clinical experience, the claims-based predictive model for ASBC had better PPV (0.78 v. 0.62) with similar sensitivity (0.39 v. 0.38). For the ASBC cohort, selected AE rates per 100 person-years included: anemia, 26.4; neutropenia, 14.3; pulmonary embolism, 5.7; and leukopenia, 4.0. Conclusions: Identification ofcancer stage and biomarkers using claims data can be improved through predictive modeling. ER+/HER2- ESBC and ASBC cohorts are being utilized for characterizing indications and conducting safety evaluations of targeted therapies. [Table: see text]
Frequency and type of JAK3 variants in adult patients with leukemia.
Authors: Benton Christopher Brent , Assi Rita , Wang Feng , Pierce Sherry , Patel Keyur , Kornblau Steven Mitchell , AlRawi Ahmed , Zhang Jianhua , Hamilton Betty Ky , Takahashi Koichi , Dinardo Courtney Denton , Futreal Andrew , Garcia-Manero Guillermo , Kadia Tapan M. , Kantarjian Hagop M. , Andreeff Michael , Verstovsek Srdan
Published: September 2018

e13117

Background: Janus kinases (JAK) family members ( JAK1, JAK2, JAK3, TYK2) are involved in tumorigenesis. JAK3 activating variants, including V722I, demonstrably induce cellular transformation in vitro. The prevalence of JAK3 variants/mutations in leukemia, particularly in AML, and their role in leukemogenesis, remains unclear Methods: We retrospectively reviewed leukemia patients (pts) treated at MD Anderson Cancer Center between 2012 and 2016, whose marrow samples were tested for JAK3 variants/mutations by next generation sequencing. We evaluated the type and prevalence of variants, the demographics, laboratory, treatment, and clinical information for JAK3 pts. Results: A total of 28 leukemia pts with JAK3 variants were identified, and included: MDS/MPN (n = 4), CLL (n = 2) and B-cell ALL (n = 1). All 7 non-AML pts had V722I variant (in the pseudokinase domain). Twenty-one AML pts were identified; this included 15 pts with V722I (1.5%) out of total 977 AML pts tested, demonstrating this variant was significantly more prevalent in AML pts than in the general population (1.5 vs 0.9%, P= 0.04). Three pts (0.3%) had P151R (FERM domain), and 1 pt each (0.1%) had V718L (pseudokinase), R925L (kinase), and L940V (kinase), none of which have been previously described. A pt with T815M (between pseudokinase-kinase domains) was identified from outside genetic testing. For AML pts, median allelic frequency for variants was 52% (range, 41-88) and median marrow blasts was 42% (range 21-97); 10% of AML patients had complex karyotype. Concomitant mutations were most commonly found in IDH1/2 (n = 10), TP53 (n = 8), FLT3 (n = 5), NPM1 (n = 5), ASXL1 (n = 5), RUNX1 (n = 4), DNMT3A (3), and TET2 (n = 3). Conclusions: We report the largest survey of JAK3 variants among adult leukemia pts, with detailed and novel variants described for AML. Given allelic frequencies, JAK3 variants may represent germline polymorphisms in most cases; however the activating V722I variant has increased prevalence among AML pts. The existence of an FDA-approved JAK3 inhibitor tofacitinib, and the prevalence and location of JAK3 variants provide a basis for additional investigations.
Virtual brain tumor histopathology and immunohistochemistry with stimulated raman scattering microscopy.
Authors: Lewis Spencer B , Pandian Balaji , Hollon Todd , Niknafs Yashar , Garrard Mia , Camelo-Piragua Sandra , Orringer Daniel A
Published: September 2018

e13511

Background: Stimulated Raman scattering (SRS) microscopy is a label-free optical technique which uses the chemical composition of fresh tissue to generate image contrast. Prior work has demonstrated exceptional correlation between SRS images and H&E microscopy for detecting brain tumor infiltration ex vivo. However, SRS has not previously been suitable for a clinical environment. Further, SRS has utilized structural, rather than chemical, diagnostic features. We present the first clinical validation of SRS, as well as our work towards mutation-targeted SRS imaging. Methods: Implementation of SRS with a fiber laser source allowed sufficient stability for clinical deployment. Unprocessed specimens from 200 neurosurgical cases were imaged at the CH2 and CH3 vibrational modes, then processed to mimic the appearance of H&E staining. 30 cases were trialed in a simulated intraoperative consultation to assess concordance between SRS and cryosection microscopy. A multi-layer perceptron (MLP) model was then used to predict brain tumor diagnosis based on quantified image attributes. To explore the potential for chemically specific SRS, isogenic lines of normal human astrocyte were prepared, differing by the presence or absence of the R132H mutation in the isocitrate dehydrogenase 1 (IDH1) gene. IDH1 R132H cells accumulate high concentrations of the oncometabolite 2-hydroxyglutarate and display predictably altered metabolism. 200 Raman spectra were collected from 50 wild type (WT) and 50 R132H cells with the aim of detecting these changes. Each cell line was then submitted for targeted metabolomic analysis. Results: Excellent concordance was observed between SRS and frozen section histology ( κ >0.89). The MLP diagnosed brain tumor subtype with 90% accuracy. A robust spectral difference was observed between wild type and R132H cells, which showed concordance with metabolomic data. Conclusions: The diagnostic capability, ease of use and speed of SRS make it well-suited for integration into the operative workflow. Further, because SRS amplifies the Raman signal with no resonant background, the spectral differences observed may allow rapid differentiation of IDH1 WT and R132H cells with SRS.
Clinical implications of next-generation sequencing in the treatment of brain cancer at a large academic institution.
Authors: Mariotti Veronica , Gonzalez Velez Miguel , Parrondo Ricardo Daniel , Leslie Lori Ann
Published: September 2018

e13521

Background: The use of next-generation sequencing (NGS) in clinical practice has increased the treatment (tx) options for cancer patients (pts). The expansion of genomic libraries used by NGS databases has resulted in increased identification of targetable genomic alterations (GAs). The aim of this study was to identify the clinical implications of genomic library expansion in the detection of GAs in pts with brain cancer at a large academic institution. Methods: We retrospectively analyzed 71 consecutive pts with brain cancer at the John Theurer Cancer Center that had NGS performed between 02/2014 and 09/2016. GAs were identified using the FoundationOne assay (Foundation Medicine, Cambridge, MA). GAs, number (n) of available genomic-directed tx and n of clinical trials were reviewed. The NGS assay interrogated 236 genes and introns of 19 genes until 09/2014, and subsequently was expanded to include 315 genes and introns of 28 genes. We compared median survival, n of GAs found, n of available trials, and n of tx available in pts who received NGS until 09/2014 (G1, n = 33) with pts who received NGS after 9/2014 (G2, n = 38). Results: Median survival was 30 months (range 19.9-40.1), median age was 62 years (range 26-82), the median n of GAs/sample was 5 (range 1-11). There was a significant positive correlation between n of GAs/sample and n of available trials and tx (r = .5, p = .00 and r = .3, p = .00, respectively). There was a negative correlation between survival and n of GAs (r = -.3, p = .02). G1 harbored 142 GAs with a median n of 4 GAs/sample (range 1-10), while G2 harbored 170 GAs with a median n of 5.5 GAs/sample (range 0-11). There was an absolute increase of 19.7% in GAs in G2 compared to G1. There was no difference in median overall survival. Conclusions: The expansion of genomic libraries increased the detection of GAs, and was positively correlated with the n of tx and clinical trials available for brain cancer pts. Survival was not affected by the expansion of the genomic library, but higher n of GAs was correlated with shorter survival. Expansions of NGS databases lead to increased n of potential tx options for brain cancer pts. Further studies are needed to investigate the impact of NGS targeted tx on survival.
Novel domain-targeted anti-Trop-2 monoclonal antibodies to elicit therapeutic synergy against multiple human cancers.
Authors: Alberti Saverio , Trerotola Marco , Relli Valeria , Pedicone Chiara , D' Amore Antonella , Dini Francesca , Fratarcangeli Silvia , Guerra Emanuela
Published: September 2018

e14002

Background: Trop-2 is a calcium signal transducer that drives tumor cell growth. Trop-2 is overexpressed in the majority of carcinomas, where it associates with worse prognosis. The Trop-2 extracellular domain contains a N-terminal cysteine-rich globular domain followed by a stem-like cysteine-less region that connects to the transmembrane domain. Trop-2 engages in homophylic interactions between adjacent cells and interacts with tight-junction proteins, which may severely affect accessibility by therapeutic monoclonal antibodies (mAb). Available anti-Trop-2 mAb mostly recognize a single immunodominant epitope between the globular and stem regions, and have limited or no therapeutic efficacy. In order to untap the potential of anti-Trop-2 immunotherapy we generated novel anti-Trop-2 mAb with tailored specificity towards the globular versus stem regions. Methods: Balb-C mice were immunized with soluble human Trop-2 produced in human 293 and murine L cell lines and in baculovirus expression system. Domain-targeted anti-Trop-2 mAb were selected by flow cytometry using live 293 transfectants.Therapeutic potential was assessed in human cancer xenografts in murine models. mAb mode of action was investigated by Western blot, live-cell imaging and in vitro ADCC and cancer cell growth inhibition assays. Results: mAb were identified that were differentially directed against the Trop-2 stem versus globular regions. These mAb efficiently bound Trop-2 expressing cancer cells and inhibited cell growth in vitro. In vivo, naked anti-globular OX-G64 and anti-stem OX-S55 mAb were most effective in inhibiting the growth of colon, ovary, breast and prostate cancers as xenografts in nude mice. NSG mice and in vitro mechanism profiling indicated efficient ADCC, together with efficient internalization for ADC development. Differential efficacy for established tumors versus isolated-cell models of metastatic dissemination was shown. Most remarkably, OX-G64/OX-S55 co-administration demonstrated sinergic growth inhibition in vivo. Conclusions: The OX-G64 and OX-S55 anti-Trop-2 mAb are novel domain-targeted, sinergic therapeutic mAb for game-changing anti-cancer immunotherapy.
Evaluation of carboplatin toxicities and efficacy using different body weight descriptors in the Calvert formula.
Authors: Jhaveri Tulip A , Gil Brigitte , Zou Mei , Hartwell Nathan , Sands Jacob
Published: September 2018

e14017

Background: Carboplatin dosing is calculated using the Calvert formula that includes glomerular filtration rate (GFR). In practice, GFR is often substituted by creatinine clearance (CrCl) with the Cockcroft-Gault (CG) equation. However, there is no standardization of which body weight descriptors should be utilized. Data suggest use of total body weight (TBW) may overestimate CrCl in overweight patients, while adjusted body weight may better estimate CrCl. The primary objective is to determine the impact of using different weight descriptors (DWD) in place of TBW for carboplatin dosing. Methods: This was a single-center, retrospective cohort study. Patients over 18 who were intended to receive at least 6 cycles of carboplatin with target area under the curve (AUC) of 5 or 6 and paclitaxel 175 to 225 mg/m2 were included. DWD included: adjusted body weight for overweight and obese patients, ideal body weight for normal weight patients and TBW for underweight patients. Primary endpoint was the composite of grade 3 or 4 anemia, thrombocytopenia and neutropenia (hematologic toxicity). Secondary endpoints included individual parameters of the primary endpoint, dose delays, dose reductions, progression-free survival, overall survival and objective response rate. Results: A total of 117 patients were included (DWD: n = 39; TBW: n = 78). Results on survival analysis, anemia and dose reductions are pending. Conclusions: To our knowledge, this is the first evaluation of patient outcomes specifically comparing carboplatin dosing calculations. Although there is a trend toward decreased grade 3 and 4 hematologic toxicities in the DWD group, there is no statistically significant difference in this under powered cohort. However, there was a significant decrease in treatment delays and days of treatment delay (p < 0.001) in the DWD group. Further studies are needed to evaluate the impact of DWD on carboplatin dosing. [Table: see text]
An easy-to-handle DPD deficiency test in saliva to identify patients at high-risk for life-threatening toxicity due to fluoropyrimidine therapy.
Authors: Schwartsmann Gilberto , Antunes Marina Venzon , Galarza Andres , Hahn Roberta Zilles , Raymundo Suziane , da Silva Anne Caroline Cezimbra , Staggemeier Rodrigo , Spilki Fernando R , Longhinoti Lidia B , Anjos Gabriel M , Franzoi Maria Alice B , Linden Rafael
Published: September 2018

e14019

Background: Severe dihydropyrimidine dehydrogenase (DPD) deficiency can be lethal in 0.5-3.0% of patients receiving fluoropyrimidines. Unfortunately, there is no routine test in medical practice to identify high-risk patients. Here, we evaluated the use of plasma and saliva uracil (U) to dihydrouracil (UH2) metabolic ratio and DPYD genotyping, as a means to identify patients with DPD deficiency and fluoropyrimidine toxicity. In addition, we report on a functional test using UH2/U metabolic ratio in dried saliva spots (DSS). Methods: Prior to fluoropyrimidine therapy, plasma and saliva samples were obtained from 60 patients with GI cancer. U and UH2 levels were measured by LC-MS/MS in plasma and saliva. Patients were also genotyped for DPYD (*7/*2A/*13/Y186C). WHO grading were used to report treatment toxicity. Results: In 21 patients (35%) toxicity was documented. For those, no variant allele carrier for DPYD was identified. The UH2/U metabolic ratios were 0.1-26.7 in plasma and 0.1-24.0 in saliva, with a higher correlation with toxicity grade in saliva as compared to plasma (rs 0.52 vs 0.28). Median metabolic ratios were lower in patients with severe toxicity as compared to those with no toxicity (0.59 vs 2.83 saliva; 1.62 vs 6.75 plasma, P < 0.01). A cut-off of 1.16 for the salivary UH2/U ratio was set (AUC 0.84) with 86% sensitivity and 77% specificity for the identification of grade 3-4 toxicity. A plasma cut-off of 4.0 (AUC 0.75) revealed a 71% sensitivity and 76% specificity. Moreover, saliva of 21 patients were applied to filter paper to obtain DSS and sent to the laboratory by regular mail. U and UH2 were stable in DSS stored at 45°C up to 7 days. In this set of patients, grade 3-4 toxicity was documented in 3/21 cases (14%), all three cases had metabolic ratios below 1.16 in DSS, confirming our prior results. Conclusions: DPYD genotyping failed to identify severe DPD deficiency, but the UH2/U metabolic ratios in saliva showed enough sensitivity and specificity to deserve further evaluation. DSS samples allowed medical oncologists working at distant sites to send us samples by post, with results available within a week. This test is being validated in a larger sample population.
Overinterpretation and misreporting of prognostic factor and biomarker studies in medical oncology.
Authors: Kempf Emmanuelle , de Beyer Jennifer , Porcher Raphael , Nguyen Long , Moons Karel , Altman Douglas , Reitsma Johannes , Hopewell Sally , Sauerbrei Willi , Collins Gary
Published: September 2018

e14023

Background: To generate empirical evidence, classify and estimate the frequency of distorted presentation and overinterpretation of results in prognostic factor (PF) studies in oncology. Methods: We selected 17 oncology journals with an impact factor of 7 or more. PubMed was searched to identify primary clinical studies evaluating one or more PFs published in 2015. Each article was independently evaluated by 2 reviewers using a data extraction form that was extensively pilot-tested. We classified aspects of overinterpretation as misleading reporting, interpretation and extrapolation. Results: Our search identified 10 844 articles, 98 met eligibility criteria. The PF was assessed prospectively in 8 of 56 observational studies, and in 16 of 42 clinical trials. The median number of PFs per study was 2 (Q1-Q3, 1-5). Overall survival was used as the outcome in 77 studies. The median number of statistical analyses reported with regards to the PF effect assessment was 42.5 per study (Q1-Q3, 15.5-86.5). Thirty-three reports reported using 2 or more different multivariable models to assess the PF effect and 21 did not adjust. Misleading reporting included selective and incomplete reporting of the PF effect (n = 26 and n = 8, respectively). The conclusions focused solely on significant results in 80 reports, and in those where there was at least one NS result, 80% of studies focused their conclusions solely on the significant results. Misleading interpretation included not reporting the PF effect within a multivariable model (n = 23 and n = 54 in full-texts and abstracts, respectively). One out of 5 conclusions used linguistic spin with strong statements in both full-text and abstract. Linguistic spin of NS results was found in 28 Results sections in the full-text and in 18 abstract conclusions. The conclusions were inconsistent with the study findings in one out of five articles (both in the full-text and abstract). Discrepancies between the conclusions presented in the full-text and in the abstract were found in 18 reports. Conclusions: Our study provides insight into the level of reporting and overinterpretation of findings that were frequently inconsistent with the results in oncology journals with high impact factors.