bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes with CDK4/6 inhibitors based on endocrine sensitivity in hormone receptor-positive metastatic breast cancer (HR+ MBC).
Authors: Jain Amit L , Mullins Janice Nhan , Poorman Kelsey Anne , Chaudhry Amina , Ranganath Harsha Avinash , Miller Emily McCollum , Valasareddy Poojitha , Smith Justin R , Ryder Julie , Winerip Michelle , Schwartzberg Lee S. , Vidal Gregory A.
Published: May 2019

e12526

Background: PALOMA-3 results demonstrated that patients (pts) with sensitivity to previous endocrine therapy had a substantial benefit with Palbociclib compared to those with intrinsic endocrine resistance (Turner NC et al. NEJM 2018). ESR1 mutation has been associated with decreased response to endocrine therapy (Fribbens C et al. JCO 2016) and NSD3 amplification in breast cancer cells have been correlated with the overexpression of ESR1 (Irish JC et al. Mol Oncol 2016). Here we demonstrate a real-world response to CDK4/6i based on high-risk features and correlation to biomarkers of response. Methods: We retrospectively analyzed 115 HR+MBC pts at a single large community cancer center who received CDK4/6i + endocrine therapy and 40 matched controls treated with endocrine therapy and underwent NextGen Sequencing (NGS) profiling of 592 genes (Caris Life Sciences, Phoenix, AZ). The primary outcome was progression-free survival (PFS). Hazard ratios were calculated from Cox proportional hazards models built using the survival package[1] in R. Results: Among 115 pts in the CDK4/6i cohort, the median PFS for pts treated in the first-line (N=77) versus (vs.) second-line (N=38) was 9.7 and 4.6 months (mo) respectively (HR 2.04, p=0.001). Further, the median PFS in first-line cases who had a Disease-Free Survival (DFS) of >2 years (endocrine sensitive) (N=27) was 11.9 mo, and in pts with DFS < 2years (endocrine resistant) (N=24), it was 7.7 mo (HR 0.71, p= 0.397). Six pts with ESR1 mutations had worse PFS compared to ESR1 wild-type (N=40) when treated with CDK4/6i in 1st line, 6.4 vs. 18 mo (HR: 2.25, p=0.052) and 2nd line 2.5 (N=9) vs. 5.6 mo (N=17) HR: 2.09, p=0.1). NSD3 amplification was the only other genomic alteration showing significance as a negative predictor of PFS (first-line: 6.1 vs. 14.7 mo, HR: 2.40, p=0.04; second-line: 2.8 vs. 6.5 mo, HR: 3.61, p=0.06). NSD3 amplification appeared to have no significant effect in the control cohort 6.5 vs. 4.4 mo, (HR 1.29, p=0.63). Conclusions: In this real-world cohort, CDK 4/6 combination therapy benefits HR+ MBC patients in the first and second-line setting. ESR1 mutation is a predictor of worse outcome. NSD3 gene amplification is a potential biomarker of resistance to CDK4/6i combination therapy. (Therneau T (2015). A Package for Survival Analysis in S version 2.38, https://CRAN.R-project.org/package=survival).
Immunohistochemical evaluation of Cyclin D1 and β-Catenin expression in subtypes of triple-negative breast cancer.
Authors: Gudtskova Tatiana N. , Vashchenko Larisa N. , Karnaukhov Nikolay S. , Kvarchiya Mramza V. , Bosenko Ekaterina S. , Saforyan Natalya S. , Luganskaya Roza G.
Published: May 2019

e12553

Background: The purpose of the study was to reveal characteristics of Cyclin D1 and β-Catenin expression in subtypes of triple negative breast cancer (TNBC). Methods: The study included 60 patients diagnosed with verified TNBC (T1N1M0/T2N0M0, ER-/PR-/Her2-). Immunohistochemical staining with CK5/6, EGFR, Cyclin D1, β-Catenin antibodies was performed. Basal-like (BL) subtype was identified when > 25% cells were CK5/6+ and/or EGFR+ (any staining). The expression of β-Catenin was assessed by its location: the membrane, cytoplasm, nucleus. Cells with negative staining on the membrane and cytoplasmic staining were counted and calculated as a percentage of the total number of tumor cells. Nuclear expression of β-Catenin was considered positive with at least 1 positively stained cell in the field of view at x200 magnification. Parametric statistical methods were used. Significance of the difference between the two means was assessed by the Student's t-test. Results: A number of TNBC samples showed Cyclin D1 overexpression. The loss of β-Catenin on the cell membrane and its abnormal accumulation in the cytoplasm was significantly more frequent in TNBC with Cyclin D1 overexpression. These processes were more pronounced in BL cancers. Loss of membrane expression in BL cancers: 29.6±6.1 and 58±7.4%; accumulation in the cytoplasm: 33.4±5.4 and 63.3±7.2%, with low and high Cyclin D1 respectively. Loss of membrane expression in non-BL cancers: 17.6±3.8 and 33.3±4.3%; accumulation in the cytoplasm: 27.3±6.3 and 49.5±8.2%, with low and high Cyclin D1 respectively. Only BL TNBC demonstrated β-catenin translocation to the nucleus (up to 20 stained cells in the field of view): in 33.3% tumors with Cyclin D1 overexpression and in 12% of tumors with its low expression. Conclusions: Levels of expression of β-catenin and Cyclin D1 in TNBC may have predictive value, and the choice of these biomarkers as targets will improve the treatment with new-generation medications.
The relationship of lncRNA NR2F1 and breast cancer angiogenesis via IL-8/lncRNA NR2F1/miR-200s/IL-8 loop.
Authors: Zhang Qi , Zhang Jin , Lu Sihong , Shao Nan , Lin Ying
Published: May 2019

e12573

Background: Angiogenesis is key for metastasis and predicts a poor prognosis in breast cancer. Among the pro-angiogenic factors, interleukin-8 (IL-8) could be secreted by tumor cells mediated by microRNA-200 family (miR-200s). Long non-coding RNA (LncRNA), was reported to absorb microRNA to play multiple roles in various diseases including breast cancer. Our preliminary results recognized lncRNA NR2F1 through Agilent Human LncRNA array from breast cancer cells overexpressing IL-8. However, the relationship between LncRNA NR2F1 and breast cancer angiogenesis remains unknown. Methods: Breast cancer cell migration, invasion, proliferation and angiogenesis were assessed by Transwell, CCK8, tube formation, and wound healing assays. The expression of LncRNA NR2F1, miR-200s and IL-8 were detected by qPCR, Western blotting and ELISA. Breast cancer metastasis and angiogenesis in vivo were measured in a zebrafish model. Results: We found that the basal expression of lncRNA NR2F1 is higher in breast cancer cell lines than it in normal cells. In vitro, lncRNA NR2F1 induced breast cancer migration, invasion, and proliferation. Meanwhile, lncRNA NR2F1 promoted human umbilical vascular endothelial cell (HUVEC) proliferation, tube formation, and migration both via breast cancer conditioned medium and via direct HUVEC transfection. In the zebrafish model, lncRNA NR2F1 promoted breast cancer cell metastasis and neo-angiogenesis. Further study disclosed that lncRNA NR2F1 downregulated the expression of miR-200s, which in turn upregulated the expression of IL-8 in breast cancer cells. Conclusions: Our findings suggest that LncRNA NR2F1, as a potential promoter of breast cancer, may induce breast cancer angiogenesis through IL-8/lncRNA NR2F1/miR-200s/IL-8 loop.
Retrospective study of neuroendocrine breast cancer cases from a single institution in Québec.
Authors: Plante Marie-Michèle , Houle Paul-Michel , Prady Catherine C. M. , Martel Samuel , Geha Sameh , Pavic Michel
Published: May 2019

e12588

Background: Within numerous breast cancer types, the neuroendocrine subtype distinguishes itself from the others by its rarity. Most of the actual data comes from European and Asian retrospective studies, whom were mostly published before the 2012 WHO classification. Methods: The aim of our study was to describe a North American cohort of neuroendocrine breast cancer tumors homogenized for the latest WHO classification of 2012. We describe the clinical presentation, diagnostic, therapeutic management and prognosis of our population recensed between 2006 and 2016 at the CHUS in Sherbrooke, Québec. A pathological review of the cases was done to unify the cohort by the latest WHO classification. Results: 59 cases were identified from the 5238 cases of breast cancer evaluated between 2006 and 2016. After review from the pathologist, 9 cases were discarded since they did not meet the diagnostic criterias. 47 patients had invasive breast carcinoma with neuroendocrine differentiation, 4 patients had poorly differentiated/small cell carcinoma and none had well differentiated neuroendocrine tumor. 44 patients were not metastatic whereas 7 patients were metastatic at disease onset with a mean age at diagnosis of 70 and 67 years respectively. 10% (4/44) developed a metastatic disease with a median time of 30 months. The mean size of the tumor was 26,1 mm and had a mean Ki67% of 28,3%. All of our patients were ER+, 98% PR+ and 4% Her2+. None had a triple negative disease. 6 patients were SBR grade 1, 31 were grade 2 and 12 were grade 3. The median follow-up for the non-metastatic patients was 42 months and 23 months for the metastatic patients. The median overall survival of our metastatic cohort was 30 months. The histologic subtype did not statistically influence the overall survival and the progression-free survival. Conclusions: Our study is the largest North American cohort of neuroendocrine breast cancer tumors classified with the latest WHO classification of 2012. More details about each subgroup analysis will be presented at the meeting. Even with this classification, the histologic diagnosis remains challenging. Further studies are needed to better characterize these patients and define their optimal management.
Prognostic value of circulating cytokines in breast cancer: A prospective study in sixty breast cancer patients in Tunisia.
Authors: Ayari Jihene Braham , Haj Ammar Shourouk , Balti Mehdi , Ben Azaiz Mouna , Zribi Aref , Fendri Sana , Ben Nasr Sonia , Ghazouani Ezzedine , Agili Faida , Kullab Sharif Ahmed , Haddaoui Abderrazek
Published: May 2019

e12592

Background: Breast cancer is the second most common cancer and the fifth most common cause of cancer mortality worldwide. The functional relationship between inflammation and cancer is an old concept of cancero- genesis, and it is now clear that inflammatory process certainly potentiates and/or promotes neoplastic risk. However, many of the molecular and cellular mechanisms mediating this relationship remain unresolved. The aim of this study is to measure the level of circulating cytokines (IL17, IL6, IL22, IL23 and TNFα) in breast cancer patients in Tunisia, and to evaluate their implication as prognostic factors. Methods: Serum samples were collected prospectively from sixty breast cancer patients in Tunisia. TNF-α and IL6 levels were determined using the technique of a solid-phase, two-site chemo-luminescent enzyme immune-metric assay (Immulite 1000, USA). Serum levels of IL17, IL22 and IL23 were measured by enzyme-linked immunosorbent assays (ELISA) sandwich method. Results: The mean age of patients is 48 years, and fourth of them were metastatic. The mean level of cytokines IL6, IL17, TNFα, IL22 and IL23 were respectively 4.80 ± 7.26 pg/ ml (min 2, max 36.80 pg/ ml), 0.27 ± 0.69 pg/ ml (min 0, max 3.62 pg/ ml), 5.93 ± 2.27 pg/ ml (min 4, max 15.30 pg/ml), 50.82 ± 34.78 p/ml (min 26.48, max 199.48 pg/ ml) and 18.05 ± 30.91 pg/ ml (min 0, max 200.21 pg/ml). Serum IL6 level was significantly higher in advanced stages (p = 0.013), especially in metastatic cases (p = 0.001) and in patients who had recurrent disease (p = 0.010). High level of TNFα was also significantly associated with advanced stage (stage III and IV) (p = 0.019), and high level of IL22 was significantly associated with a high histopathological grade (Grade III of Bloom-Richardson grade (SBR)) (p = 0.028). IL23 was found to be significantly increased in lymph node metastatic cases (p = 0.042) and in young patients < 35 years (p = 0.034). Finally, the level of IL17 was significantly higher in patients who had recurrent disease (p = 0.018). Conclusions: Our results highlight the role of certain circulating cytokines as potential prognostic biomarkers in breast cancer patients. The serum analysis of these cytokines, which could contribute to tumor growth and progression, may help to identify groups of patients with poor prognosis and who may need more aggressive treatment. This correlation needs to be evaluated in large prospective validating trials and suggests a rational for the development and use of cytokine blockade in treatment of some groups of breast cancer patients.
Use of a granulocyte colony-stimulating factor for the prevention of febrile neutropenia in the era of value-based care.
Authors: Feinberg Bruce A. , Lord Kevin , Kish Jonathan , Laney Jalyna R. , Chopra Dhruv , Liassou Djibril
Published: May 2019

e12601

Background: Value based care design is intended to encourage responsible use of medical resources to optimize cost effective delivery of quality patient care. Febrile neutropenia (FN) is a potentially life-threatening condition associated with myelosuppressive chemotherapy (chemo). Clinical guidelines and product label recommend granulocyte colony stimulating factors (G-csf) use for the primary prevention of FN in patients with clinically significant FN risk. This study evaluated the real-world use of primary prevention pegfilgrastim (PPP), a sustained release G-csf, in metastatic breast cancer (mBC) patients. Methods: Patients who had initiated systemic chemo from Jan-2013 to Dec-2017 were identified from a third-party, administrative claims database using medical and pharmacy claims (ICD-9/10 codes for both BC and metastases) were selected. Patients who received any HER2 and/or any oral or infused hormonal therapies, or had another malignant diagnosis, were excluded. FN risk: low < 10%, moderate 10-20% and high > 20%, was assigned to chemo drugs/regimens using multiple source data (e.g. Lexicomp). If patients received combination chemo, the assigned risk level was the highest risk of any individual agent. Patients administered a moderate or high FN risk (MHR) regimen were considered at “significant clinical risk”. The frequency of use of PPP in MHR and in low FN risk (LR) was calculated per line (L) of therapy. Results: 10,342 patients met the selection criteria. Mean age at initiation of treatment was 61.7 years (SD = 12.12). Total number of patients with exposure to MHR regimens were 4,601 (44%). By line of therapy, the proportion of patients prescribed PPP was: 1L MHR = 32%, 1L LR = 1%; 2L MHR = 12%, 2L LR = 1%; 3L MHR = 6%, 3L LR = 1%; 4L MHR = 6%, 4L LR = < 1%; 5L MHR = 5%, 5L LR = < 1%; and 6L MHR = 6, 6L LR = 1%. Conclusions: The observed rate of PPP use with LR chemo was exceptionally low and consistent with cost effective, high quality, evidence-based medicine. PPP use with MHR chemo was in the minority and declined with consecutive lines of treatment suggesting the need to study clinical outcome variances in mBC patients receiving MHR chemo with and without PPP.
SeqPlus sequencing methodology enables robust whole-genome sequencing, true variant detection, and novel genomic insights from archival esophageal carcinoma FFPE samples.
Authors: Bailey Shannon Terrell , Hicks Belynda , Zhu Bin , Hu Nan , Taylor Phil R. , Gulcher Jeffery R , Sun Hongye , Lund Jim , Oliner Kelly , Williams Richard T. , Chanock Stephen J. , Goldstein Alisa M.
Published: May 2019

e13016

Background: Whole-genome sequencing (WGS) of formalin-fixed, paraffin-embedded (FFPE) samples could enable novel insights from archival sample collections, yet robust FFPE WGS is challenged by fragmented DNA, uneven genomic coverage & sequencing artifacts attributed to FFPE fixation. We report our proprietary extraction & library preparation methodology (SeqPlus) with high quality, uniform WGS sequencing performance comparable to that from fresh-frozen samples. Methods: We analyzed 20 paired esophageal carcinoma (EC) samples i.e., primary tumors & matched germline samples to assess SeqPlus performance on 10-15-year-old FFPE tissues, measure variant concordance between WGS and a high-depth sequencing panel (269 genes, 400x coverage) & identify novel genomic features. Results: At a targeted 70x WGS tumor sequencing depth, 93% of the genome was covered by ³ 20 reads, 99% of bases had 10x coverage & average duplicate reads were 31%. We noted similar transition/transversion ratios & mutational spectra as from fresh-frozen EC specimens, suggesting that extraction & library preparation contributes to prior FFPE artifacts. Concordance of tumor-specific SNVs & indels derived from WGS & targeted panel was high at 86%. All 76 targeted panel-detected variants above the WGS limit of detection (mutant allele frequency [MAF] > 10%) were detected by WGS, 2 variants (2 tumors) were detected only by WGS, and 12 variants at MAF ≤ 6% (9 tumors) were only detected by the targeted panel. Tumor WGS yielded SNV, indels & CNV findings beyond variants detected by targeted sequencing. WGS enabled detection of 10.4 putative cancer variants per tumor compared to 12 variants per patient from frozen specimens and a median of 7 (up to 16) cancer-associated variants in genes outside the targeted panel. WGS copy number analysis revealed CCND1, EGFR, TP63, and SOX2amplification, CDKN2A/B deletion and additional unrecognized genomic aberrations. Conclusions: Our study reinforces the utility of high-quality, uniform WGS sequencing of archival FFPE cancer samples with SeqPlus and unlocks the potential for massive-scale retrospective genomic analysis of archived pathology samples with associated clinical & outcomes data.
The targetable mutation landscape of Chinese patients with non-small cell lung cancer.
Authors: Li Jun , Zhang Cuiyun , Zhao Jiuzhou , Wang Zhizhong , Wei Bing , Sun Rui , Groen Harry J.M. , Ma Jie , Guo Yongjun
Published: May 2019

e13018

Background: In recent years, the prognosis of non-small cell lung cancer (NSCLC) patients has been substantially improved by targeted therapies against specific molecular aberrations, i.e. tyrosine kinase inhibitors (TKIs) for Epidermal Growth Factor Receptor ( EGFR) etc. Several genes have been suggested by NCCN guideline (v7.2017) to test for NSCLC patients, including EGFR, ALK, ROS1, BRAF, MET, RET, HER2 and KRAS. The aim of this study is to profile the landscape of actionable mutations in Chinese NSCLC patients. Methods: From 2015 to 2017 621 treatment naïve NSCLC patients enrolled in the affiliated cancer hospital of Zhengzhou University were included in this analysis. DNA was extracted from the FFPE biopsies of these patients and processed for target capture sequencing covering the exons and flanking splicing regions of the 8 genes suggested by NCCN guideline, as well as introns of ROS, ALK and RET. Results: In total, 593 out of the 621 NSCLC patients harbor one or more mutations in these 8 genes, accounting for 95.5% of all the cases. EGFR, ALK and HER2 are the top 3 mutants, with a frequency of 52%, 32% and 26% respectively. Genetic aberrations in BRAF, MET, ROS1, KRAS and RET occur in 22%, 18%, 16% and 14% of the patients. The most common variation is missense; T > G, C > T and C > A changes are more often observed than T > C, T > A and C > G; the median number of variants per sample is 2, ranging from 1 to 13. There are 418 mutations detected on EGFR, of which 206 (49.28%) are clinically relevant. EGFR L858R, Exon19 deletion, Exon20 insertion, G719, A750P were observed in 123 (29.43%), 43 (10.29%), 8 (1.91%), 6 (1.44%) and 6 (1.44%) cases respectively. Gene fusions were identified in 78 cases, and the EML4- ALK is the most common one occurred in 54 patients, other fusion genes include KIF5B- ALK (11) ， CCDC6- RET (4), CD74- ROS1 (4), EZR- ROS1 (2), ERC1- RET (1), , SDC4- ROS1 (1) and TCOF1- ROS1 (1). Conclusions: Target sequencing of the 8 genes suggested by NCCN guideline for NSCLC patients reveals essential information for designing personalized therapeutic regimen. Chinese patients, maybe other Asian countries also, may benefit more from this molecular testing, because of the high occurrence of actionable mutations.
Clinical genomic profiling to identify actionable alterations for very early relapsed triple-negative breast cancer patients in Chinese population.
Authors: Hong Ruoxi , Qinglian Zhai , Yuan Zhongyu , Xia Wen , Xu Fei , Wang Shusen
Published: May 2019

e13031

Background: Triple negative breast cancer (TNBC) represents about 19% of all breast cancers in Chinese population. Compared with other breast cancer subtypes, TNBC tend to be more aggressive and is associated with early relapse and worse survival. In this study, we performed comprehensive genomic profiling to explore the clinical relevant genomic alterations (CRGAs) and potential therapeutic targets in very early relapsed TNBCs, regarding as tumor recurrences within 24 months. Methods: Formalin-fixed paraffin-embedded (FFPE) tumor tissue specimens from 23 very early relapsed TNBC patients were tested by FoundationOne CDx (F1CDx), a next generation sequencing based diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB). Results: In total, 137 CRGAs were detected in all the 23 TNBC patients, averaging 6 alterations per sample. The mean TMB was 4 Muts/Mb, and only one patient was MSI-Intermediate. The top ranked altered genes were TP53 (83%), PTEN (35%), RB1 (30%), PIK3CA (26%), BRCA1 (22%), NOTCH1 (13%), MYC (13%) and CCND1 (13%). Notable co-segregating amplifications included KAS-KDM5A and FGF3-FGF4-FGF19. Importantly, we detected one patient with ERBB2 amplification and one patient with ERBB2 exon20 insertion, both of them were missed by immunohistochemistry (IHC). We also detected novel alterations of ROS1-EPHA7 fusion and EGFRvIVa in the first time, which has not been reported in breast cancer before. Furthermore, we also found EGFR amplification with copy number equal to 126 in one TNBC patient. In addition, 61%, 52%, 43%, 22% and 17% TNBC patients have at least one CRGA in pathways involving PI3K/mTOR, Cell cycle, DNA repair, Growth factor receptors (GFRs) and RAS/MAPK signaling pathways, respectively. Importantly, alterations in RAS/MAP tended to occur in very early-stage, such as IA-IIB tumors, and GFRs tended to occurr in IIIA-IIIC tumors. Furthermore, 100% of these patients have at least one CRGA and 87% patients have at least one actionable alteration. Conclusions: This study demonstrated that most of TNBCs have at least one actionable alteration. In conclusion, incorporating F1CDx into TNBC may shed light on novel therapeutic opportunities for these very early relapsed TNBC patients.
Germline mutation PTCH2 1172-1173delCT in Chinese population with early-onset breast cancer.
Authors: Li Lixi , Li Chunxiao , Ma Fei , Qian Haili , Guan Xiuwen , Yi Zongbi , Liu Binliang , Zhai Jingtong , Li Yanchen , Suo Ying , Mo Hongnan , Xu Binghe
Published: May 2019

e13049

Background: Early-onset breast cancer has more aggressive clinicopathological characteristics and worse prognosis. The peak age of breast cancer in China is about 40 years old, 10 years ahead of that in Europe and the United States. PTCH2 was characterized as susceptibility gene in early-onset breast cancer by whole exons sequencing in preliminary work. PTCH2 performs as a tumor suppressor in the Hedgehog signaling pathway, but it has never been reported in breast cancer. Methods: 259 women with early-onset breast cancer and 571 women with non-early-onset breast cancer with peripheral blood samples were included for genetic testing. According to the ACMG guidlines, PTCH2 1172-1173delCT was defined as likely pathogenic mutation. To make an in-depth exploration of the function and molecular mechanism of PTCH2 gene, we performed experiments at molcular, cellular and animal level. Results: The frequency 2.3%(6/259)of PTCH2 germline mutation in early-onset breast cancer was significantly higher than that(2/571) in non-early-onset breast cancer( P ＜ 0.05), and increased with the age at diagnosis younger. Bioinformatics analysis showed that the patients with lower expression of PTCH2 had worse prognosis. PTCH2 knockout cells lines promoted the cell proliferation and enhanced the ability of colony formation and tumorigenic ability of nude mice. Furthermore, the expression level of pten in the PTCH2 knockout cell lines was significantly downregulated. Conclusions: Patients with PTCH2 1172-1173delCT mutation had aggressive clinicopathological characteristics and worse prognosis. As a tumor suppressor gene, PTCH2 may promote the incidence of early-onset breast cancer by downregulating the expression of pten and cross-regulating Hedgehog and PI3K/AKT signaling pathways. PTCH2 could be acted as a diagnostic and prognostic biomarker for early-onset breast cancer.
Lung cancer: Improving screening in rural clinic.
Authors: Le Thuy Thanh Thi , Johnson-wall Helen , Hu Katherine
Published: May 2019

e13060

Background: Lung cancer is the leading cause of overall cancer-related deaths in both men and women in the United States. In 2009, cancer surpassed cardiovascular disease as the leading cause of death in North Carolina. Between 2010-2014, the age-adjusted incidence rate for lung and bronchus cancers in North Carolina was 70 per 100000 persons per year. Between 2010-2014, the age-adjusted mortality rate for lung and bronchus cancers in North Carolina was 50.6 per 100000 persons per year. It is documented that about half of lung and bronchus cancer cases were diagnosed at the distant stage and about 60 percent of deaths occurred in adults ages 65-84. In 2011, 32 percent of cancer death was from lung/bronchus cancer in Robeson County. A chart review in a rural primary care clinic identified patients not being appropriately screened for targeted intervention. Methods: Our retrospective chart review at Lumberton Medical Clinic, a rural outpatient Internal Medicine Clinic, reviewed 91 records from adults aged 55 to 80 years old during the timeframe of September 2017 through August 2018. Patients with a known history of lung cancer were excluded from this study. Patient records were assessed for compliance with USPTF lung cancer screening guidelines. USPTF recommends adults aged 55 to 80 who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years to have an annual low-dose computed tomography of the chest to screen for lung cancer. Results: The review showed that during the timeframe studied, 42% of patients who qualified received appropriate screening, while 58% of those qualified were found to have no documentation of screening. Following data analysis, intervention to increase screening rates has been initiated. This involves provider education, posters, and individualized letters mailed to patients found deficient during the study. The success of this direct patient outreach effort will be measured over six months. Conclusions: It is the responsibility of providers to emphasize the importance of proper lung cancer screening. This retrospective review found that a large percentage (58%) of adults were not being adequately screened in our rural clinic. Direct outreach is underway to increase compliance rates in this high-risk population served by our rural clinic.
Breast Cancer Cases in a Surveillance Program: Report from the Hereditary Department at South General Hospital, Sweden.
Authors: Karumo Anna-Maria , Thorén Linda , Von Wachenfeldt Väppling Anna
Published: May 2019

e13068

Background: Women with a doubled, or greater, lifetime risk of developing breast cancer are according to Swedish guidelines offered intensified surveillance with one or more of the following modalities; mammography (MG), ultrasound (US) and magnetic resonance imaging (MRI). MRI is primarily recommended for mutation carriers < 55 years of age. From 2014 mutation carriers undergo annual surveillance, alternating MRI and MG/US every 6 months. Aim: To evaluate which modality was able to detect the tumor, tumor stage and characteristics in women who developed breast cancer under surveillance at the Hereditary Department, South General Hospital, Stockholm. Methods: Data on women in the surveillance program diagnosed with breast cancer 2003 - 2018 was collected from patient notes. Results: Fifty-five women were diagnosed with breast cancer. Twenty-five women underwent MRI, in 22 cases the tumor was visible. Forty percent of the women aged 55 or older had tumors only visible on MRI. Fifty-three women underwent US, in 38 cases the tumor was visible. Thirty two of 49 tumors were detected by MG. In 35 cases the tumor was not palpable. Fourteen women were diagnosed with DCIS. These cases, combined with patients with T1 N0 tumors, constituted 69% of the 55 women. Eleven women were node positive. Twelve women were diagnosed in between screening rounds, ie interval cancers. Three of these were small tumors found only at the pathology examination after prophylactic mastectomy. The proportion of interval cancers decreased from 31% to 14% after 2014. Twenty-four women were identified as mutation carriers in BRCA1, BRCA2 or PALB2. Seven of these mutations were detected after the patient´s cancer diagnosis. Nine mutation carriers were diagnosed with interval cancers, four were node positive. Conclusions: All women were diagnosed at a potentially curable stage and most were node negative. Mutation carriers constituted the largest portion of women with interval cancers. This study indicates that MRI may be of benefit in the surveillance of mutation carriers after 55 years of age. The transition from annual to biannual examinations with MG/US and MRI appears to decrease the incidence of interval cancers.
Complex multimorbidity, perceived life expectancy, and routine cancer screening receipt: Differences between older women and men.
Authors: Koroukian Siran M. , Warner David F
Published: May 2019

e13071

Background: Complex multimorbidity (MM) predicts poor health outcomes. How MM predicts preventive health services receipt, such as cancer screening, is less clear. Yet cancer screening decision making involves not only clinical presentation (MM) and age, but also patients’ perceptions about need. We hypothesize that patients’ perceived life expectancy (PLE) moderates the effect of MM and age on cancer screening receipt (mammography for women and prostate screening for men). Methods: Data came from 20,705 women and men, ages 52-90, from the 2002-2012 waves of the U.S. Health and Retirement Study. Receipt of screening mammogram (women) or “examination of [the] prostate to screen for cancer” (men) in the last two years were binary (0/1) measures. MM was an ordinal count (0-3) of the co-occurrence of any chronic conditions, functional limitations, and geriatric syndromes. Age was measured in years. PLE was the chance respondents’ thought they would live 10-15 more years (0 = 0% - 10 = > 90%). Additional control variables included self-rated health, race/ethnicity, socioeconomic status, marital status, smoking, BMI, and other preventive services (e.g., flu shot) receipt. We used survey-adjusted repeated measures logistic regression to predict screening receipt separately by gender. Results: Women reported higher MM and PLE than men. Greater MM reduced the likelihood of mammography receipt. However, women with MM who had greater PLE had an increased likelihood of mammography receipt. Furthermore, mammography receipt decreased more slowly with age for women with high PLE. For men, greater MM did not lead to reduced prostate screening. Men’s PLE was not associated with screening nor did it modify the effects of MM or age. Conclusions: Greater PLE increases likelihood of cancer screening for women even when MM and advanced age would recommend against. Men’s clinical presentation and subjective perceptions of longevity are not associated with prostate screening receipt. We speculate that the differences in the nature of the screening tests combined with greater public awareness of breast cancer create conditions where subjective perceptions are more likely to affect mammography decision-making.
A three-year epidemiological profile of cancers managed by a Haitian cancer program from 2016 to 2018.
Authors: Bernard Joseph , Alexis Lynn Gabrielle , Pierre Lenz Sacha Christyl , DeGennaro Vincent
Published: May 2019

e13079

Background: The recent epidemiology of cancers in Haiti is poorly understood, since there is no functional national cancer registry. The data from GLOBOCAN 2012 and 2018 are estimations that do not reflect the actual cancer burden in Haiti. The aim of this study was to present the three-year epidemiology of cancer cases managed by a cancer program in Port-au-Prince, Haiti. Methods: A retrospective study was conducted on patients aged 15 years old or more with pathological and/or clinical diagnosis at the cancer clinic of Innovating Health International (IHI) from January 2016 to December 2018. The chart review collected variables such as age, gender, date of diagnosis, cancer type and outcome to present this epidemiological profile of cancers. Results: One thousand four hundred and eighty-one (1481) cancer cases were managed during this study period, respectively 282 in 2016, 513 in 2017 and 686 in 2018 (p < 0.001). 84% of the patients were female and 16% male. The mean age of the study population was 51.8 years [15 –92], ranging from 51.7 years in 2016 to 52.1 years in 2018 (p = 0.56). Adolescents and young adults (15-39 years old) represented 20.9% of this cohort and geriatric cases (≥ 65 years old) 19.6%. Breast cancer was the most common type (n = 686, 46.3%), followed by gynecological cancers (n = 330, 22.3%) with cervical cancer representing 70.9% of the cases, gastrointestinal cancers (n = 138, 9.3%), hematological malignancies (n = 75, 5.1%), head and neck cancers (n = 64, 4.3%), sarcomas (n = 40, 2.7%), urological cancers (n = 32, 2.2%), skin cancers including melanoma (n = 29, 2%), lung cancer (n = 13, 0.9%), thyroid cancer (n = 10, 0.7%) and central nervous system (CNS) cancers (n = 2, 0.1%). 4.2% of the patients (n = 62) had a cancer of unknown primary (CUP). Breast cancer was the most common type among women (54.7%) and gastrointestinal cancers the most diagnosed among men (25.3%). There was a predominance of women for most of the cancer types. The overall mortality rate was 31% and 8.6% of the patients were lost to follow-up. Conclusions: There was a significant increase of cancer cases in our cancer clinic from 2016 to 2018, likely due to a combination of our cancer awareness campaign, increased diagnosis and referral. Cancer mainly affects Haiti’s young, feminine and active population. Breast and cervical cancers were the most prevalent in this retrospective cohort. The under-representation of prostate and other urological cancers, lung cancer, acute leukemias and CNS cancers was likely due to underdiagnosis, misdiagnosis, under-referral or early mortality.
Gender differences in relative survival among patients with primary peritoneal carcinoma.
Authors: Ananthula Aneesha , Govindarajan Rangaswamy , Sharma Rohan
Published: May 2019

e13092

Background: Primary peritoneal cancer(PPC) is a very rare aggressive cancer and is usually diagnosed late due to which it is generally portrays a poor prognosis. There are very few retrospective studies with limited knowledge about PPC. NCCN treatment guidelines for PPC is the same as that of ovarian cancer. Methods: We used 18 registries from Surveillance, Epidemiology, and End Results database to identify 6570 patients with Primary peritoneal carcinoma from 2000 to 2012 with follow up period upto 2015. Actuarial method was used to calculate 1 and 3 year Relative Survival (RS). Covariates included age, sex, race and grade. Results: PPC occurs more commonly in women with about 93% of the cases documented in women and about 88% of those documented in white women as per this database. The 1-year and 3-year RS for white women was 77.7% and 46% versus 69.6% and 54.1% for white males respectively. Males with grade I and grade II cancers had a better 3-year RS of 88.1% and 64.6%, in comparison with females with 77.3% and 55% respectively. Females with grade III and Grade IV cancers had a better 3 -year survival of 47.9% and 49% versus males who has a RS of only 35.3% and 39%. RS was significantly better in patients < 60 years with 3-year RS rate of 60.9% versus 36.4% for patients > 70 years. 3-year RS rates at during 2000-04, 2005-09 and 2010-14 were similar with 43.8%, 48.7% and 48.5% respectively. Conclusions: PPC is treated in a similar manner to epithelial ovarian carcinoma given some of its similarities in biological and pathological behavior. The cause of primary peritoneal cancer in unknown and there are only few studies done due to paucity of cases. Over the years survival seems to have not changed significantly and we need more clinical trials to identify the best course of treatment. [Table: see text][Table: see text][Table: see text][Table: see text]
Non-interventional study OVATAR final report: Diagnostic and treatment approaches in Russian ovarian cancer population—BRCAm group analysis.
Authors: Tyulyandina Alexandra , Kekeeva Tatiana , Gorbunova Vera , Kolomiets Larisa , Statsenko Galina , Saevets Valeria , Khokhlova Svetlana Victorovna , Tkachenko Svetlana , Koroleva Irina , Lisyanskaya Alla Sergeevna , Bakashvili Oksana , Novikova Olga , Krikunova Ludmila , Solovieva Ekaterina , Ponomarenko Dmitry , Zagumennova Lyubov , Tsimafeyeu Ilya , Vedrova Olga , Karaseva Vera , Tjulandin Sergei
Published: May 2019

e13111

Background: First large Russian ovarian cancer observational study was conducted in 2014-2018. Methods: A total of 500 patients in 29 sites in Russia with newly diagnosed ovarian, peritoneal and fallopian tube cancer was enrolled (NCT02122588). The primary objective was to describe treatment approaches in the first line treatment. 141 patients (pts) with BRCA1/2 mutations (BRCA1/2mt) detected by NGS in blood and tissue were observed prospectively during at least 2 years. Results: Rate of BRCA1/2 mutations in Russian population is high – 28.4% (141 from 496 available for any testing). 77.6% (388/500) underwent biomarkers blood testing prior to treatment. CA-125 was positive in 99.7% (387/388), 15.2% (59/388) of pts had positive CA19-9, CA72-4 - in 2.3% (9/388). Positive CEA was presented in 15.2% (59/388). This marker was detected more frequently in BRCA2mt pts subgroup (28.0% (7/25)) than in BRCA1mt pts: 9.0% (8/90) (p = 0.05). 26.6% (133/500) of all study population had an oncology family history; 44.0% (62/141) BRCA1/2mt pts had relatives with oncological diseases and 19.7% (70/355) in BRCA wild type pts (p = 0.0001). 98.6% (139/141) of BRCA1/2mt pts received first line therapy. Objective response rate was registered in 79.8% (111/139) pts. Progression after platinum based regimens was observed in 53.6% (59/110) BRCA1mt pts and 44.8% (13/29) BRCA2mt pts. 35.6 % (21/59) of BRCA1mt pts had platinum-refractory and platinum-resistant relapses, while 15.4% in BRCA2mt subgroup (2/13) (p = 0.64). Platinum-sensitive relapses were in 64.4% (38/59) BRCA1mt pts and 84.6% BRCA2mt (11/13) (p = 0,64). Median PFS in BRCA1/2mt pts was 25.5 months. Among BRCA1/2mt pts underwent cytoreduction median PFS in subgroup without visible residual tumor was 36.4 months and in subgroup with residual tumor < 1 cm 15.3 months. Conclusions: In this large-scale prospective non-interventional study diagnostics and treatment approaches in Russian ovarian cancer pts were evaluated and high frequency of BRCA1/2mt was observed. Pts with BRCA1/2mt had better prognosis and most of them had platinum-sensitive relapses after first line chemotherapy that allowed platinum-based regimen rechallenge.
Risk of arterial thromboembolic events (ATEs) with tyrosine kinase inhibitors (TKIs) used in renal cell carcinoma: A systematic review and meta-analysis.
Authors: Farooq Muhammad Zain , Mathew Jessey , Malik Saad , Mukthinuthalapati V V Pavan Kedar , Asghar Noureen , Riaz Anum , Cheema Zarish , Riaz Irbaz Bin , Zahoor Haris
Published: May 2019

e13119

Background: Tyrosine kinase inhibitors (TKIs) are routinely used in the treatment of metastatic RCC and Sunitinib is approved for the use in adjuvant setting. Arterial thromboembolic events (ATEs) have been described with these agents, although the overall risk remains unclear. We did a systematic review and meta-analysis to determine the incidence associated with the use of FDA approved TKIs used in treatment of RCC. Methods: PubMed, EMBASE, Cochrane Central and Scopus databases were searched to identify phase 2 and 3 RCTs of TKI therapy in RCC. Trials were included if they reported ATEs defined as arterial thrombosis, cerebral ischemia or infarction, myocardial ischemia and myocardial infarction. The DerSimonian-Laird random effects meta-analysis was performed using CMAv3 software to derive pooled estimates of incidence rates of ATEs with its 95% confidence interval (CI). I2 statistic was computed to express the percentage of the total observed variability due to study heterogeneity. Risk for bias was assessed using the Cochrane Collaboration’s tool. Results: 1755 studies retrieved in the initial search, and 13 phase 2 and 3 clinical trials (n = 4983) were included in the quantitative analysis. The trials had open label design which can potentially result in bias. Risk of bias was low in all other domains. TKIs used for the treatment of RCC included sunitinib (n = 2632), sorafenib (n = 981), cabozantinib (n = 78), pazopanib (n = 844), axitinib (n = 189) and tivozanib (n = 259). The incidence of ATEs with the use of TKIs was 2.9% (95% CI: 2-3%). Cabozantinib was associated with the highest rate of ATEs (11.5%, 95% CI: 6-21%), followed by sunitinib (2.6%, 95% CI:2-3%) pazopanib (2.6%, 95% CI:2-4%) and axitinib (2.1%, 95% CI: 1-6%). The TKI with lowest event rate of ATE was tivozanib (0.8%, 95% CI:0.2-3%). Conclusions: The use of TKIs is associated with increased risk of developing ATEs. Clinicians should be aware of the possibility of increased ATEs and counsel the patients about this increased risk to enhance the process of informed decision making.
HIV associated head and neck cancers in an inner-city minority population.
Authors: Katiyar Vatsala , Araujo Tiago , Gupta Shweta , Rubinstein Paul G. , Rosen Fred R.
Published: May 2019

e13124

Background: Head and Neck Cancer (HNC) is a common non-AIDS defining malignancy and its risk increases by 1.7 to 4-fold with HIV infection. Little is known about the epidemiology and outcomes in this subset of patients. This study was undertaken to evaluate the characteristics of HIV+ HNC in an inner city minority population. Methods: All patients with a diagnosis of HNC from January 2008 to December 2017 were identified from the Tumor Registry Database of Cook County Health. We screened patients for HIV+ status at the time of HNC diagnosis. Retrospective chart review of those with Squamous cell carcinoma (SCC) was performed and compared to the largest reported HIV+ HNC cohort (SPORE consortium – J Acquir Immune Defic Syndr. 2015; 65(5):603-10). Other histologies were not included. Results: A total of 1379 charts were screened and 38 unique HIV+ patients with SCC were identified. The most common tumor sites were oral cavity (34%), larynx (26%) and oropharynx (26%), similar to SPORE. However, our cohort had a higher number of African Americans (AA) and a greater proportion of female patients. The median age of diagnosis was 52 years, which is similar in both studies but much lower than the non-HIV population (SEER database - median age 65). Over 63% had an undetectable viral load (VL) compared to 1.4% in SPORE, but the median CD4 count did not differ (298 vs 300 cells/µL). Survival information was available for 27 patients, with a median of 21 months (mo) versus 49 mo in SPORE. Overall survival (OS) was higher in non-smokers (34.5 mo vs 21 mo) and those with CD4>500 when compared to CD4<100 (42mo vs 15mo) Table summarizes the comparison of data. Conclusions: HIV+ HNC was predominantly seen in AA males. When compared to the SPORE cohort, OS was much poorer in the inner city minority, despite similar median age and CD4 counts. In addition, smokers and those with CD4 <100 cells/µL at diagnosis seem to have worse outcomes. [Table: see text]
A pharmacogenetic analysis of peripheral sensory neuropathy related to administration of taxanes in breast cancer patients.
Authors: Leonard Alyson , Gudena Vinay K.
Published: May 2019

e13133

Background: Commonly used in the treatment of breast cancer, the taxane class includes paclitaxel and docetaxel. Both medications are primarily metabolized by cytochrome P450 enzymes and transporters mediate drug membrane influx and efflux. Variability in metabolizing enzymes and drug transporter function can affect drug clearance. This study sought to determine if the presence of pharmacogenetic changes in metabolizing enzymes and transporters resulted in a patient experiencing peripheral sensory neuropathy. Methods: In this case-control study, patients were enrolled between April 13, 2018 and April 30, 2018. Electronic medical records of patients with current appointments at Cone Health Cancer Center- Wesley Long were reviewed to identify patients who completed treatment with taxanes for breast cancer after January 1, 2017 for evaluation for inclusion in the study. Buccal swabs for pharmacogenetics testing were collected. Genes of interest, ABCB1, CYP3A4, CYP3A5, and SLCO1B1, were evaluated and data was categorized by phenotype. Baseline characteristics and phenotype results were compared using Fisher's exact test for categorical variables and Wilcoxon Rank Sum for numeric variables as appropriate. Results: Thirty-three patients were included in the final analysis. The population was mainly white at 72% and all patients in the study were female. The average patient age was 57 years old. Most patients had stage 1 breast cancer. Most patients received docetaxel. Among patients with peripheral sensory neuropathy, nine were grade 1, five were grade 2, and seven were grade 3. Resulting phenotypes: CYP3A5, all patients were normal metabolizers. CYP3A5, 7 normal metabolizer, 4 intermediate, and 22 poor. SLCO1B1, 25 normal function, 8 intermediate, and no low. ABCB1, 13 normal function, 7 intermediate, and 13 low. For all genes, there was no statistically significant difference in phenotype between the neuropathy and no neuropathy study arms, CYP3A5 (p = 0.075) SLCO1B1 (p = 0.106), ABCB1 (p = 0.902). Conclusions: The findings of our study indicate that having pharmacogenetics changes in the genes, ABCB1, CYP3A4, CYP3A5, and SLCO1B1 did not influence the patients experience with peripheral sensory neuropathy.
Genomic profiling for unfavorable carcinoma of unknown primary patients.
Authors: Lu Hsueh-Ju , Liu Hsuan , Hang Jen-Fan , Chao Yee , Chen Ming-Huang , Liu Chun-Yu , Huang Chi-Ying F. , Chang Mu-Hsin
Published: May 2019

e13140

Background: Cancer of unknown primary site (CUP) is the seventh prevalent cancer around the world. Whether most CUP patients share a distinct molecular genome-phenotype is unclear. Methods: A total of 179 unfavorable CUP patients were retrospectively enrolled from Taipei Veterans General Hospital between Jan 2000 and Dec 2009. 33 qualified FFPE samples were sequenced by 275 target gene panel (QIAseq Human Comprehensive Cancer Panel [DHS-3501Z], QIAGEN). Identified significant variants were enriched by using DAVID software (https://david.ncifcrf.gov/). Results: Among 33 patients’ samples, total 6816 variants, including SNP and INDEL from both germline SNPs and somatic mutations were enrolled. After clustering, 112 variants which accounted for 1.64% were selected. Somatic and germline variants were 63.4% (71/112) and 36.6% (41/112), respectively. Profiles between these two groups were different after enrichment that pathway in cancer (fold enrichment [FE] = 6.64, P = 7.03E-09) is most important for somatic mutation and lysine degradation (FE = 25.6, P = 3.78E-04) for germline SNPs (Table). Conclusions: This genomic profile provides new insight into unfavorable CUP patients. Further studies between genotypes vs. phenotypes and drug targets vs. genotypes are warranted.[Table: see text]