bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4097: TMV vaccine inhibits growth of squamous cell carcinoma of head and neck in mice
Authors: Bommireddy Ramireddy , Munoz Luis , Pack Chrstopher D. , Ramachandiran Sampath , Reddy Shaker JC , Kim Janet , Chen Georgia , Saba Nabil F. , Shin Dong M. , Selvaraj Periasamy
Published: August 2019

Introduction: Head and neck cancer is a leading cause of cancer related deaths accounting for approximately 3% of all cancer related mortalities in the US. Currently, there is no cure for the advanced squamous cell carcinoma of the head and neck (SCCHN) thus development of efficacious therapies is urgently needed. To test whether vaccine-induced immunity inhibits tumor growth, we investigated efficacy of a tumor membrane-based vaccine immunotherapy in a murine SCCHN (SCC VII) model.

Materials and Methods: The SCC VII tumors grown subcutaneously in C3H/HeJ mice were harvested to generate tumor membrane vesicles (TMVs). TMVs were then protein transferred with glycolipid-anchored immunostimulatory molecules mouse GPI-B7.1 and mouse GPI-IL-12 to generate the TMV vaccine. Mice were vaccinated with TMV vaccine either before (prophylactic) or after SCC VII tumor cell challenge (therapeutic) and tumor growth was monitored every 3 days. Survival was then assessed using a Kaplan-Meier survival curve and significance determined using a Log-rank test for comparison analysis.

Results: SCCVII cells express MHC I, CD44, CD47 and respond to IFN-γ in vitro. The therapeutic TMV vaccine inhibited tumor growth and improved the survival of mice challenged with SCCVII tumor cells. Tumor-free mice remained protective from rechallenge with SCCVII cells.

Conclusions: These observations suggest that tumor tissue-based vaccines can be harnessed to develop an effective immunotherapy for SCCHN.

Funding: Supported by Head and Neck SPORE pilot funding from Emory Winship Cancer Institute.

Citation Format: Ramireddy Bommireddy, Luis Munoz, Chrstopher D. Pack, Sampath Ramachandiran, Shaker JC Reddy, Janet Kim, Georgia Chen, Nabil F. Saba, Dong M. Shin, Periasamy Selvaraj. TMV vaccine inhibits growth of squamous cell carcinoma of head and neck in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4097.
Abstract 4114: NPM1 upregulates the transcription of PD-L1 and suppresses T-cell activity in triple negative breast cancer
Authors: Long Qian , Li Yizhuo , Qin Ge , Zhang Changlin , Shi Dingbo , Chen Miao , Shi Shuihan , Zhang Kefang , Deng Wuguo
Published: August 2019

Programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) interaction plays a crucial role in tumor-associated immune escape. Here we verified that triple-negative breast cancer (TNBC) had higher PD-L1 expression than other subtypes. We then discovered that nucleophosmin (NPM1) bound to PD-L1 promoter specifically in TNBC cells and activated PD-L1 transcription, thus inhibiting T cell activity in vitro and in vivo. Furthermore, we demonstrated that PARP1 suppressed PD-L1 transcription through its interaction with the nucleic acid binding domain of NPM1, which was required for the binding of NPM1 at PD-L1 promoter. Consistently, the PARP1 inhibitor olaparib elevated PD-L1 expression in TNBC and exerted a synergistic effect with anti-PD-L1 therapy. Together, our research has revealed NPM1 as a novel transcription regulator of PD-L1 in TNBC, which could lead to potential therapeutic strategies to enhance the efficacy of cancer immunotherapy.

Citation Format: Qian Long, Yizhuo Li, Ge Qin, Changlin Zhang, Dingbo Shi, Miao Chen, Shuihan Shi, Kefang Zhang, Wuguo Deng. NPM1 upregulates the transcription of PD-L1 and suppresses T-cell activity in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4114.
Abstract 4115: Naturally circulating anti-LAG3 antibodies exist in cancer patients
Authors: Tsimafeyeu Ilya , Ershov Pavel , Kaluzhskiy Leonid , Couture Jean-Philippe , Gagnon Hugo , Kuznetsov Vladimir , Kalachev Aleksei , Ivanov Alexis , Bratslavsky Gennady
Published: August 2019

To date there was no evidence of existence of the naturally circulating antibodies to checkpoint receptors in humans. LAG3 checkpoint is crucial in modulation of immune response that is altered in humans with inflammatory and malignant conditions. We have previously described novel methodology in identification of diagnostic and therapeutic antibodies (US Patent #9810694). Here we report identification of novel potentially therapeutic fully human anti-LAG3 antibodies in cancer patients.

Anti-LAG3 antibody presence was evaluated in 25 individuals: 11 healthy donors (controls) and 14 cancer patients in two different laboratories blinded to clinical information. Surface plasmon resonance analysis was done using the optical biosensor BiacoreT200 where LAG3 protein was covalently immobilized on the optical chip and biosensor signals from human serum samples were analyzed. Western Blotting used recombinant LAG3 loaded on a 10% SDS PAGE followed by blotting with plasma samples followed by biotinylated anti-human IgA/IgG/IgM and IrDye 800 streptavidin. Plasma anti-LAG3 IP utilized recombinant LAG3 crosslinked to MagResyn Carboxyl beads followed by incubation with plasma, followed by a biotinylated anti human IgA/IgG/IgMand IrDye streptavidin. No anti-LAG3 antibodies were detected in control group.

Among three assays there was complete correlation for presence of anti-LAG3 antibody in 3 cancer patients. One of these patients had sufficient plasma quantity and anti-LAG3 concentration (21 - 33 µg/ml) that should allow for the antibody purification and de novo sequencing. The novel fully human anti-LAG3 antibody will be identified, purified, and the sequence will be determined.To our knowledge this is the first report of checkpoint antibody presence in humans. Further study with cloning and evaluation of therapeutic properties of novel fully human anti-LAG3 antibody in xenograft models will be performed.

Citation Format: Ilya Tsimafeyeu, Pavel Ershov, Leonid Kaluzhskiy, Jean-Philippe Couture, Hugo Gagnon, Vladimir Kuznetsov, Aleksei Kalachev, Alexis Ivanov, Gennady Bratslavsky. Naturally circulating anti-LAG3 antibodies exist in cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4115.
Abstract 4128: Identification and characterization of LHC165, a TLR7 agonist designed for localized intratumoral therapies
Authors: Deane Jonathan A. , Cortez German A. , Li Chun , Eifler Nora , Kasibhatla Shailaja , Parikh Nehal , Pan Shifeng , Bender Steven
Published: August 2019

Checkpoint inhibition has transformed immunotherapy by alleviating T cell exhaustion in a subset of patients. However, an important component of effective immune targeting to expand the benefit of immune response requires engagement of both innate and adaptive responses. Our understanding of safe and effective engagement of the innate immune system is evolving, with multiple preclinical and clinical agents targeting pathways such the Toll-like Receptors. Here we disclose the structure and preclinical activity of LHC165, a benzonapthyridine TLR7 agonist that is adsorbed to aluminum hydroxide. The interaction between LHC165 and aluminum hydroxide allows for a slow release from the injection site resulting in improved efficacy in mouse models compared with free LHC165. This localization allows for immune activation at the site of the tumor and also results in lower systemic exposure and cytokine induction. Intratumoral studies in syngeneic preclinical studies show single agent activity and a benefit when dosed in combination with checkpoint blockade. LHC165 as a single agent and in combination with PDR001 is currently enrolling patients with advanced malignancies in CLHC165X2101.

Citation Format: Jonathan A. Deane, German A. Cortez, Chun Li, Nora Eifler, Shailaja Kasibhatla, Nehal Parikh, Shifeng Pan, Steven Bender. Identification and characterization of LHC165, a TLR7 agonist designed for localized intratumoral therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4128.
Abstract 4129: Novel small molecule TLR7/8 agonists for enhancing NK cell-mediated ADCC
Authors: Khanna Vidhi , Kim Hyunjoon , Zhang Wenqui , Larson Peter , Ferguson David , Panyam Jayanth
Published: August 2019

Antibody-dependent cell-mediated cytotoxicity (ADCC) is a key mechanism of action for some therapeutic antibodies. ADCC involves killing of an antibody-coated target cell by an effector cell through the release of cytotoxic or cell death-inducing molecules. ADCC is triggered through interaction of Fcγ receptors present on the effector cell surface with the Fc region of the target-bound antibody. Natural killer (NK) cells are one of the primary effector cells that mediate ADCC. There is significant interest in designing therapeutic agents that can enhance ADCC because this can result in improved clinical responses with approved antibodies. We have developed a suite of highly substituted imidazoquinolines, which activate TLR 7 and/or 8 and induce significantly higher levels of cytokines compared to the FDA-approved TLR7 agonist imiquimod. In the current study, we evaluated our series of TLR7-specific, 8-specific and 7/8 dual selective agonists for their ability to improve ADCC with Cetuximab. We investigated NK cell activation in the presence of these compounds, as well as NK cell mediated ADCC against an EGFR expressing lung cancer cell line, A549. In addition, we also measured cytokine induction in human peripheral blood mononuclear cells in response to these compounds. Our studies show dual TLR 7/8 and 8-specific agonists induce robust pro-inflammatory cytokine secretion and activate NK cells. however, mixed agonists also induce greater immunosuppressive cytokines compared to TLR8-specific agonists. Further, these agonists also significantly enhanced Cetuximab mediated ADCC in vitro. In vivo studies examining the anticancer efficacy of the combination of selected TLR7/8 agonists and Cetuximab are ongoing.

Citation Format: Vidhi Khanna, Hyunjoon Kim, Wenqui Zhang, Peter Larson, David Ferguson, Jayanth Panyam. Novel small molecule TLR7/8 agonists for enhancing NK cell-mediated ADCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4129.
Abstract 4137: Circulating TGFâ and TNFá in metastatic breast cancer patients treated with eribulin. The TRANSERI project
Authors: Garrone Ornella , Nigro Cristiana Lo , Michelotti Andrea , Montemurro Fillippo , Vandone Anna Maria , Abbona Andrea , Paccagnella Matteo , Falletta Antonella , Genua Elena , Angelis Claudia De , Tonissi Federica , Vanella Paola
Published: August 2019

Background: Eribulin (E) is approved for the treatment of metastatic breast cancer (mBC) patients (pts) after failure of antracyclines and taxanes. E interferes with microtubule leading to apoptosis and G2/M cell cycle arrest. In human cancer cell lines and in mice, it reverses epithelial mesenchimal transition (EMT) and reduces metastases in mice. TGFβ, an immunosuppressive cytokine, acts as growth factor for cancer-associated fibroblasts (CAFs) and promotes EMT. TNFα synergizes with TGFβ to promote EMT. The TRANSERI study investigates the modifications of TGFβ and TNFα levels in 40 mBC pts treated with E.

Methods: Plasma levels of TGFβ and TNFα were determined by ELISA assay at baseline, before cycle (C) 3, 5 and at disease progression in mBC pts treated with E at 1.23 mg/m2, d 1-8 every 21 d. Statistical analysis of the changes in the longitudinal samples was performed by GraphPad 5. Clinical outcome was monitored according to standard internal follow up procedure.

Results: We report analyses in pts who completed 5 C or progressed before C 5. So far, we have evaluated TGFβ level in 34 pts and TNFα in 26 pts. The median (M) basal TGFβ value was higher in pts than in 9 healthy volunteers (201.9 pg/ml vs 115.1 respectively). At C 5, 14 pts had a decrease in TGFβ with a M value approaching the one of healthy controls (161.9 pg/ml vs 115.1 pg/ml respectively). 19 pts progressed before C 5. Overall 26/33 pts experienced progression. The M value of TGFβ in pts at progression was 293.4 pg/ml. A significant difference of TGFβ was observed between non progressed vs progressed pts (p=0.021). The M TNFα value at baseline was higher in pts than in healthy volunteers, even if in both groups it was close to the lower sensitivity cut-off of the assay. Altogether 20/26 pts experienced progression, that occurred before C 5 in 14 out of them.Intriguingly, at C 5, the TNFα / TGFβ ratio was significantly lower in pts who did not progressed compared to the value at progression (p=0.048).

Conclusions: TGFβ levels changed during treatment with E and correlate with outcome. We are evaluating the role of tumor burden in modulating the TNFα / TGFβ ratio. Definitive data will be presented.

Citation Format: Ornella Garrone, Cristiana Lo Nigro, Andrea Michelotti, Fillippo Montemurro, Anna Maria Vandone, Andrea Abbona, Matteo Paccagnella, Antonella Falletta, Elena Genua, Claudia De Angelis, Federica Tonissi, Paola Vanella. Circulating TGFâ and TNFá in metastatic breast cancer patients treated with eribulin. The TRANSERI project [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4137.
Abstract 4138: Understanding the effects of NF-kappaB signaling on macrophage phenotype to inform therapeutic approaches
Authors: Glass Evan B. , Hoover Alyssa , Harris Whitney , Mirafzali Zahra , Giorgio Todd D. , Wilson Andrew , Yull Fiona
Published: August 2019

It is recognized that modulation of macrophage phenotypes within the tumor microenvironment has the potential to achieve anti-tumor outcomes. However, formulating a strategy to achieve the benefits of such an approach in a cell-specific manner while minimizing off-target or uncontrolled deleterious side effects remains a challenge. We hypothesize that modulation of Nuclear Factor Kappa-B (NF-kappaB) signaling within macrophages in the proximal tumor microenvironment represents an effective approach. However, there remains controversy whether NF-kappaB signaling in macrophages induces pro- or anti-tumor outcomes. Understanding the mechanisms by which this signaling pathway defines predominant macrophage characteristics is therefore critical in order to use strategic interventions to obtain therapeutic benefits. Our goal is to gain insight into how to modulate NF-kappaB signaling in macrophages to generate anti-tumor phenotypes and to use this information to develop new treatments. We use immortalized bone marrow-derived macrophages or ex vivo macrophages in cell culture approaches to investigate impacts of modulation of NF-kappaB signaling on macrophage phenotypes. We have three methods to modulate signaling: doxycycline inducible transgenic mice, liposomal delivery of the bacterial cell mimic MTP-PE, and optimized polymeric nanoparticle-mediated delivery of siRNA targeting the NF-kappaB inhibitor. In addition to our in vitro assays, we also employ in vivo murine models of ovarian and breast tumor progression. This multi-faceted approach is providing insights into how altering NF-kappaB signaling in macrophages impacts their interactions with tumor cells and other cells in the tumor microenvironment. Our data suggests that high levels of NF-kappaB signaling in macrophages induce both direct tumor cell-killing and immune-stimulating responses. These studies are designed to better understand the mechanisms by which NF-kappaB regulates macrophage functions to inform development of a novel macrophage-based immunotherapy that will be effective across a wide spectrum of solid tumors and metastatic disease.

Citation Format: Evan B. Glass, Alyssa Hoover, Whitney Harris, Zahra Mirafzali, Todd D. Giorgio, Andrew Wilson, Fiona Yull. Understanding the effects of NF-kappaB signaling on macrophage phenotype to inform therapeutic approaches [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4138.
Abstract 4157: Idenitificaiton of pathogenic germline variants of patients with double primary cancer of stomach and colon
Authors: Choi Yoon Young , Park Ji Soo , Lee Seung-Tae , Shin Su-Jin , Lee Jae Eun , Jo Jeong-Hyeon , Nam Eun Ji , Son Taeil , Kim Hyoung-Il , Hyung Woo Jin , Noh Sung Hoon , Cheong Jae-Ho
Published: August 2019

Purpose: The incidence of multiple primary cancers has increased as survival of cancer patients has improved. The most common type of multiple primary cancers is the combination of stomach and colon cancer in Korea. Patients affected by two primary cancers at early age would be mainly related to their own genetic risk, however, germline variant of patients with double primary cancer have not been well evaluated.

Methods: Patient who is with pathologically confirmed cancers in both stomach and colon in Severance hospital between January, 2000 and December, 2016 were enrolled in this study. The patients were classified into two groups: early-age group was defined as both cancers were diagnosed before 55-years, and others were considered as late-age group. The overall early-age group (n=19) and randomly selected a fourth of late-age group (n=36) were enrolled in this study. The DNA was extracted from an archived formalin fixed paraffin embedded normal mucosa that was retrospectively reviewed. Target sequencing analysis focused on 65 genes that are known to be related to hereditary cancer was conducted. The characteristics of both cancers and family history were also evaluated.

Results: Overall 11 pathogenic/likely pathogenic germline variants (PGVs) were detected in nine patients (16.4%, 9/55, MLH1 [n=7], BLM [n=1], BRCA1 [n=1], MSH6 [n=1], and MSH2 [n=1]). The incidence of PGVs was 36.8% (7/19) and 5.6% (2/36) in early and late-age group, respectively (p<0.001). The early-age (Odds ratio[OR]: 9.92, 95% confidence interval [CI]: 1.81-54.49, p=0.008), Amsterdam_II criteria (OR: 24.29, 95% CI: 2.45-241.36, p=0.006), multiple lesions either gastric and colon cancer (OR: 13.13, 95% CI: 2.48-69.55, p=0.002) and mucinous/poorly differentiated histology of colon cancer (OR: 10.75, 95% CI: 1.48-78.06, p=0.019) were significant risk factors of PGVs in patients with double primary cancer at stomach and colon.

Conclusions: The Lynch syndrome related PGVs were identified in patients with double primary cancer at stomach and colon. Patients with double primary cancers at stomach and colon related to early age, multiple lesions, family history especially Amsterdam_II criteria, and poorly differentiated histology of colon cancer would be good candidate for genetic evaluation.

Citation Format: Yoon Young Choi, Ji Soo Park, Seung-Tae Lee, Su-Jin Shin, Jae Eun Lee, Jeong-Hyeon Jo, Eun Ji Nam, Taeil Son, Hyoung-Il Kim, Woo Jin Hyung, Sung Hoon Noh, Jae-Ho Cheong. Idenitificaiton of pathogenic germline variants of patients with double primary cancer of stomach and colon [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4157.
Abstract 4168: Identify the predisposition genes to endometrial cancer
Authors: Chiang Yu-Cheh , Lee Ting-Fang , Lin Yung-Feng , Weng Hui-Ying , Tsai Shih-Feng , Wu Cheng-Wen
Published: August 2019

Endometrial carcinoma is the most dominant gynecological tumor worldwide. Familial risk of endometrial cancer has been reported but little is known about the predisposition genes. Here we focused on a family with high incidence of cancer, aiming to identify potential markers with low allele frequency and high disease-causing probability. Whole-genome sequencing was performed with available DNA from 4 family members: one healthy control and 3 endometrial cancer patients. We analyzed the non-synonymous variations in the coding region expressed in 3 of the patients but not in the healthy control. The variations with high allele frequencies in Taiwanese population were excluded. Five potential candidates, KMT2D, PCDHA8, COG5, RAPGEF3 and PFDN1, were identified as heterozygous mutations predisposed to endometrial cancer. In addition, we demonstrated that PCDHA8 and COG5 genes play crucial roles in cell proliferation in endometrial cancer cells. Notably, KMT2D (lysine methyltransferase 2D) is highly mutated in the tumors of endometrial cancer. An interaction between mutated KMT2D and other candidate genes may explain the high risk of cancer formation in this family. These results validate the potential markers of endometrial cancer and create opportunities for therapeutic applications and personalized prevention.

Citation Format: Yu-Cheh Chiang, Ting-Fang Lee, Yung-Feng Lin, Hui-Ying Weng, Shih-Feng Tsai, Cheng-Wen Wu. Identify the predisposition genes to endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4168.
Abstract 4171: Identification of individuals with colonic polyposis in a highly inbred region
Authors: Lajus Tirzah Braz Petta , Timoteo Ana Rafaela
Published: August 2019

Familial adenomatous polyposis (FAP), also known as colonic polyposis, is a hereditary autosomal dominant disease, responsible for only 1% of colorectal cancer (CRC) in the population. FAP patients with a germline mutation in the APC gene have a 100% risk of developing CRC. MAP (Mutyh associated polyposis) is the polyposis associated with biallelic mutations in the MUTYH gene, and carriers are at risk of developing CRC. Few studies propose heterozygous Mutyh mutation is associated with high risk for breast cancer, but the results are conflicting. In the city Caicó, Brazil, we identified 8 non-related breast cancer patients with the same mutation c.536A>G, p.Tyr179Cys. In this region we find high frequencies of consanguineous marriages, which varied from about 9% to 32%, suggesting a direct association to genetic diseases. We hypothesize the founding mutation MUTYH_c.536A>G was established during Dutch colonization in Brazil between 1620 and 1650. For this, we are developing a population-based, case-control study of all newly diagnosed breast cancer in this city. In our group we have one oncologist, one psychologist and one geneticist. We recruited the patients (index-cases) from the archives in the Laboratory of Pathology at the Hospital Liga contra o Cancer and we invited the individuals to participate in the research.

Citation Format: Tirzah Braz Petta Lajus, Ana Rafaela Timoteo. Identification of individuals with colonic polyposis in a highly inbred region [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4171.
Abstract 4179: Identification of BRCA1 and BRCA2 mutation spectrum and their founder effect in epithelial ovarian cancer from Middle East
Authors: Siraj Abdul K. , Bu Rong , Iqbal Kaleem , Siraj Nabil , Alrasheed Maha , Ghazwani Laila , Masoodi Tariq , Parvathareddy Sandeep Kumar , Al-Kuraya Khawla S.
Published: August 2019

Epithelial ovarian cancer (EOC) remains the most fatal gynecological malignancies. Germline mutations in Breast Cancer susceptibility gene 1 and 2 (BRCA1 and BRCA2) have previously been estimated to contribute to 13-18% of all EOC. The prevalence and influence of BRCA1 and BRCA2 mutations in EOC in Middle Eastern population is not fully explored. Ethnic differences of ovarian cancer genomics have prompted us to investigate the spectrum of BRCA1 and BRCA2 mutations among our Middle Eastern EOC patients. To characterize the prevalence of BRCA mutations in our patients, BRCA mutation screening was performed in over 400 unselected ovarian cancer patients using Capture and/or Sanger sequencing. Seventeen short tandem repeat (STR) markers were used for founder mutation analysis. A total of 19 different types of pathogenic mutations were identified in 50 cases (40 mutant cases in BRCA1 and 10 in BRCA2). Nine mutations were recurrent accounting for 80% (40/50) of all mutant cases (9.8% (40/407) of the entire cohort). Haplotype analysis carried out on all unrelated cases with these mutations revealed only two (c.4136_4137 delCT and c.1140 dupG) sharing the same haplotypes thus representing founder Saudi mutations. Remarkably, lifetime risk estimation for these founder mutations appears to approach 100% given their complete absence in healthy controls. BRCA1 mutant cases were significantly associated with positive family history (p <0.0001), grade 3 tumors (p = 0.0003) and loss of BRCA1 protein expression (p <0.0001). 85.0% (34/40) of all BRCA1 mutant cases were of serous histology. BRCA2mutant cases were associated with loss of BRCA2 protein expression (p=0.0102) and a trend towards younger age (p=0.0505). Identification of the mutation spectrum, prevalence and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment and development of cost-effective screening strategy.

Citation Format: Abdul K. Siraj, Rong Bu, Kaleem Iqbal, Nabil Siraj, Maha Alrasheed, Laila Ghazwani, Tariq Masoodi, Sandeep Kumar Parvathareddy, Khawla S. Al-Kuraya. Identification of BRCA1 and BRCA2 mutation spectrum and their founder effect in epithelial ovarian cancer from Middle East [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4179.
Abstract 4186: Aggressive prostate cancer among men in Pennsylvania: Differences between Appalachian and non-Appalachian counties
Authors: McDonald Alicia C. , Wasserman Emily , Lengerich Eugene J. , Raman Jay D. , Geyer Nathaniel , Hohl Raymond , Wang Ming
Published: August 2019

Introduction: The incidence of prostate cancer (PC) is known to vary within Appalachia, with Northern Appalachia and Southern Appalachia having higher and lower rates, respectively. However, the geographical disparity for aggressive PC has not been investigated. The objective of this study was to determine whether having more aggressive PC was associated with residing in an Appalachian/non-Appalachian county and rural/urban community.

Methods: A cross-sectional study was conducted among men, aged > = 40 years, who had a primary, clinical PC diagnosis identified in the Pennsylvania Cancer Registry between 2004 and 2014. PC aggressiveness was defined as less aggressive (Gleason score 6 or 7 [3+4] and clinical/pathologic tumor stage T1-T2) and more aggressive (Gleason score > = 7 [4+3], clinical/pathologic tumor stage T3-T4, or distant metastasis) PC. Logistic regression analysis was used to examine the association between having aggressive PC (less vs more aggressive PC - dependent variable) and residing in a geographical region (Appalachian versus non-Appalachian county - independent variable), stratified by rural/urban, after adjusting for age, race, ethnicity, insurance status, marital status, serum PSA, positive lymph node status, and cancer treatment.

Results: There were 94,264 PC cases, aged 40 to 105 years, included in the study. The majority of the PC cases were white (83.9%) followed by black race (10.7%). PC cases from urban Appalachian counties (35.42%) had the highest frequency of aggressive PC followed by rural non-Appalachian (34.18%), rural Appalachian (32.12%), and urban non-Appalachian counties (32.08%). In urban areas, Appalachian PC cases were more likely to be aggressive compared to non-Appalachian PC cases, after adjusting for confounders (odds ratio [O.R.] =1.16; 95% confidence interval [C.I.], 1.13-1.21). Conversely, in rural areas, Appalachian PC cases were less likely to be aggressive compared to non-Appalachian PC cases, after adjusting for confounders (O.R. =0.91; 95% C.I., 0.85-0.98).

Conclusion: Differences in having more aggressive PC was observed for Appalachian populations by rural/urban status, with urban Appalachian PC cases more likely and rural Appalachian PC cases less likely to have more aggressive disease, compared to their non-Appalachian counterparts. Further investigation on the underlying mechanisms of aggressive PC in urban Appalachia in PA is warranted.

Citation Format: Alicia C. McDonald, Emily Wasserman, Eugene J. Lengerich, Jay D. Raman, Nathaniel Geyer, Raymond Hohl, Ming Wang. Aggressive prostate cancer among men in Pennsylvania: Differences between Appalachian and non-Appalachian counties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4186.
Abstract 4189: Limited-versus-extensive staging system for small cell prostate cancer
Authors: Syed Salman , Ali Faisal , Basourakos Spyridon , Gong Zimu
Published: August 2019

Introduction: Small cell prostate cancer (SCPC) is one of the most common extrapulmonary small cell cancers as well as one of the most common histology type among non-adenocarcinoma prostate cancers. While small cell lung cancer follows a limited-versus-extensive staging system which is different from the stage I to IV system used for non-small cell lung cancer, the prostate adenocarcinoma staging system is used in SCPC despite its distinct clinical feature and aggressive disease course. Limited by the rarity of SCPC, the optimal staging strategy for SCPC remains unknown. The present study aimed to investigate the prognostic value of limited-vs-extensive staging system in SCPC patients.

Method: The Surveillance, Epidemiology, and End Results database was used to analyze the incidence and outcome of small cell prostate cancer. Patients diagnosed between the year 2004 through 2015 were included. Limited stage is defined as those without metastasis regardless of degree of local invasion. Extensive stage is defined as any metastasis to locoregional lymph node, to distant lymph node, or to distant organs.

Result: A total of 364 SCPC patients are included in the study cohort, accounting for 0.05% of all prostate cancer cases (n=665,054). Age adjusted incidence of SCPC was 0.959 per 1,000,000 per year over the whole study period. The median age at diagnosis of SCPC is 71 years. The median overall survival is 9 months. In the 322 patients with known metastasis status, 243 (75.5%) patients are in extensive stage, whereas 79 patients are in limited stage. Patients in extensive stage are more likely to have PSA level greater than 20 than those in limited stage (26.3% vs 6%), but a similar proportion of patients in both groups have PSA level less than 4 (44.3% vs 40.0%). Compared to patients with extensive stage, those with limited stage disease had a significantly better overall survival (17 months vs 9 months, p<0.001) as well as disease specific survival (28 months vs 11 months, p<0.001). Limited stage patients with different T stage had a similar overall survival (p=0.43). Similarly, all extensive stage patients had similar outcome despite different types of metastasis (p=0.40). Multivariable analysis of treatment showed that only chemotherapy is associated with improved survival in extensive stage disease with HR of 0.46.

Conclusion: SCPC patients can be staged to limited stage and extensive stage based on the absence versus presence of metastasis. T stage in limited stage patient and type of metastasis in extensive stage patient is not associated with different outcome.

Citation Format: Salman Syed, Faisal Ali, Spyridon Basourakos, Zimu Gong. Limited-versus-extensive staging system for small cell prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4189.
Abstract 4193: Epidemiological and clinical description of head and neck cancer cases in Bogotá, Colombia
Authors: Perdomo Sandra P. , Rodriguez Paula A. , Hakim Jose A. , Avello Yubelly , Suarez David A. , Escallón Alberto , Ospina Vanessa , Useche Nicolás , Muñoz Alvaro , Baldion Margarita , Palau Mauricio
Published: August 2019

In 2018, almost 36,477 new head and neck cancer (HNC) cases were estimated to occur in South America. Colombia presents an intermediate age-standardized rate per 100,000 of 178.8 for both sexes. However, the incidence has not decreased in the las 10 years. Here, we present a description of the epidemiological and clinical characteristics of HNC patients studied in a private institution in Bogotá, Colombia. Between November 2014 and October 2018, 73 HNC cases were enrolled in the InterCHANGE- project: HNC in Latin America (http://interchange.iarc.fr/index.php). All cases had information on sociodemographic and lifestyle factors and complete clinical data. Stage at diagnosis was based on the 8th TNM AJCC classification. Inmmunohistochemical HPV studies included evaluation of p16INK4a (Clone E6H4). Mean age of diagnosis was 66 (SD 11.8), 66% of cases were male, 64% identified themselves as mestizos, 66% had superior complete educational level. 41% were nonsmokers, 56% former smokers and 52% current drinkers. 64% reported ever practiced oral sex. Tumors were mostly localized in the oral cavity (41.1%) and the oropharynx (41.1%), followed by larynx (16.4%) and hypopharynx (1.3%). 45% of cases were diagnosed at stage I and surgical treatment of primary tumor was performed in 66% of cases. Overall, 45% of cases were p16 positive. Interestingly, 93% of oropharyngeal cases were p16 positive, majority male (82%) with a mean age of diagnosis of 63 (SD 11.8) and among them, only 34% were nonsmokers. After a 2-year period of follow-up 82% of all cases were alive.In our population alcohol consumption and HPV infection are the major lifestyle risk factors associated to HNC. Oropharyngeal tumors were predominantly associated to HPV infection. Stage at diagnosis and percentage of survival is higher from what has been reported in other South American populations.

Citation Format: Sandra P. Perdomo, Paula A. Rodriguez, Jose A. Hakim, Yubelly Avello, David A. Suarez, Alberto Escallón, Vanessa Ospina, Nicolás Useche, Alvaro Muñoz, Margarita Baldion, Mauricio Palau. Epidemiological and clinical description of head and neck cancer cases in Bogotá, Colombia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4193.
Abstract 4195: Clinical, endoscopic and histological aspects of colorectal cancer at the CHU de Cocody
Authors: Fohom Serge Franck Roland Fonkoua
Published: August 2019

Introduction: The colorectal cancer (CRC) is the 4th cancer in Côte d’Ivoire (WHO 2014). Its overall prevalence appears to be advancing in sub-Saharan Africa over the years. The CRC frequently occurs at an early age and is very often discovered at an advanced or even late stage, with a bad prognosis.

Aims: To assess the clinical, endoscopic and histological aspects of CRC.

Patients and methods: An observational retrospective study was conducted from the reports of lower GI (LGI) endoscopies performed at the GI Endoscopy Unit between 2008 and 2018. The diagnosis of CRC was retained on the basis of the macroscopic and/or the histological aspect of the tumor. The following parameters were collected : number and indication of LGI endoscopies, age, gender, macroscopic appearance, location and histological type of the tumor.

Results: Over the study period, 2118 LGI endoscopies were carried out. We found 145 CRCs, corresponding to an endoscopic prevalence of 7%. The annual prevalence was 18,13 cases. A CRC was diagnosed every 14,6 LGI endoscopies performed. The sex ratio was 1,42. Median age was 56 years, with extremes of 14 and 92 years. Patients younger than 40 years (with a median age of 32 years) accounted for 18% of cases. Rectorrhagia was the main cause of LGI endoscopies found in 48 patients (33,1%), followed by an imaging discovery (ultrasound and/or abdominal CT scan) of a colorectal tumor in 38 patients (27,2%), abdominal pain or constipation in 15,3% of cases (21 patients), weight loss in 13 patients (9,5%), abdominal or anorectal mass in 8% of cases (11 patients), chronic diarrhea in 8% of cases (11 patients), metastatic tumor liver in 9 patients (6,6%), melaena in 4,4% of cases (6 patients) and anemia in 3 patients (2,2%). Macroscopically, rectal localization was the most common with 42,36% of cases, followed by sigmoid (36,1%), cecum (16,7%), right colon (11,8%), colon transverse (7%) and left colonic angle (2,8%). The ulcerative-budding form was the most common (88,65%), with strictures in 57,5% of cases and necrotic-hemorrhagic in 48,23% of cases; followed by the polypoid form (4,25%). There were no ulcerative and infiltrative form. The histological type was found in 30 patients (4,83%). Adenocarcinoma was the most common (93,3%). Stromal tumor was found in 3,3% of the cases.

Conclusion: This work confirms that the prevalence of CRC has increased in Côte d’Ivoire, that it occurs at an early age and that it is discovered at an advanced stage. This work highlights the importance of screening for CRC as early as possible in front of a Rectorrhagia, even in young patients.

Citation Format: Serge Franck Roland Fonkoua Fohom. Clinical, endoscopic and histological aspects of colorectal cancer at the CHU de Cocody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4195.
Abstract 4199: HPV prevalence of cervical cancer in the United States 2014-2015
Authors: Mix Jacqueline M. , Unger Elizabeth , Querec Troy , Thompson Trevor , Greek April , Tucker Thomas , Lynch Charles , Peters Edward , Saraiya Mona
Published: August 2019

INTRODUCTION: To determine the prevalence of human papillomavirus (HPV) types in invasive and in situ cervical cancers identified in three US population-based cancer registries (PBCRs) approximately 10 years after HPV vaccine implementation.

METHODS: Archived tissue from invasive cervical cancer (ICC) and cervical carcinoma in situ (CCIS) diagnosed between 2014 and 2015 were identified from three PBCRs in Iowa, Kentucky, and Louisiana. HPV genotyping was performed using Linear Array (Roche Diagnostics); follow-up testing of HPV-negative samples was done with INNO-LiPA HPV Genotyping Assay (Innogenetics). Type-specific weighted HPV prevalences among ICC and CCIS were estimated using the hierarchical proportion to HPV 16 and 18 oncogenic genotypes included in all vaccine formulations (16/18) and protection from five additional types in the 9-valent vaccine (31/33/45/52/58). Comparisons were made with a similar study of seven PBCRs with cervical tumor tissue obtained from diagnoses between 1994 and 2005.

RESULTS: A total of 363 ICC and 350 CCIS were successfully genotyped. Prevalence of HPV16/18 and HPV31/33/45/52/58 types were: ICC: [16/18: 69%, 31/33/45/52/58: 10%] and CCIS: [16/18: 68%, 31/33/45/52/58: 22%]. HPV prevalence in the 1994-2005 study was: ICC (n=777): [16/18: 67%, 31/33/45/52/58: 14%] and CCIS (n=481): [16/18: 61%, 31/33/45/52/58: 22%]. No overall changes were observed in the prevalence of HPV16/18 and HPV31/33/45/52/58 between the two studies.

CONCLUSIONS: Given the long latency period of HPV-related cancers, continuing to monitor HPV prevalence in invasive and in situ cervical cancers will be important for evaluating the impact of the HPV vaccine on genotype prevalence.

Citation Format: Jacqueline M. Mix, Elizabeth Unger, Troy Querec, Trevor Thompson, April Greek, Thomas Tucker, Charles Lynch, Edward Peters, Mona Saraiya. HPV prevalence of cervical cancer in the United States 2014-2015 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4199.
Abstract 4202: Identifying predictors of racial disparities in mortality among Blacks and Whites diagnosed with breast cancer in South Carolina
Authors: Babatunde Oluwole Adeyemi , Adams Swann A. , Eberth Jan M. , Felder Tisha M. , Moran Robert , Truman Samantha , Alvarado Christian , Hebert James
Published: August 2019

Introduction: Mortality among White breast cancer (BrCA) patients is 7% lower in South Carolina (SC) and is 29% higher among Black BrCA patients in SC compared to the national average. The aim of this study was to identify predictors of racial disparities in mortality among Black and White BrCA patients in SC.

Methods: Breast cancer cases were obtained retrospectively from the SC Central Cancer Registry, linked with administrative data from a private payor insurance and Medicaid Plan from 2002 to 2010. The main outcome variable was mortality which was operationalized by vital status and total survival time. The main exposure variable was patient race (White vs Black). Cox proportional hazard analyses were conducted to compare hazard ratios among Blacks and Whites to identify predictors of mortality. In assessing the relationship between race and mortality, we examined marital status, urbanicity, region, and Best Chance Network enrollment as potential effect modifiers. The multivariable model was stratified by the effect modifier variables and a backward elimination process was utilized to obtain the best fitting model among models with the following covariates: age, year of diagnosis, hormone-receptor status, stage, and grade.

Results: A total of 2155 breast cancer patients (nWhites=1557; nBlacks= 598) were reported in the study period. Adjusting for cancer stage, the hazard ratio of mortality was 3.45 (1.64,7.25) among Black women who lived in the Low Country region of the state compared with White women who lived in the Low Country region of the state. In the other three regions of the state (Midlands, PeeDee and Upstate); there were no statistically significant differences between Blacks with Whites. Adjusting for cancer stage and grade showed that the hazard ratio of mortality was 1.53 (1.04,2.26) among Black women who lived in urban areas compared with White women who lived in urban areas. There were no differences between Blacks and Whites who lived in rural areas.

Conclusions: Mortality was higher among Blacks who lived in the Low Country region of the state and among Blacks who lived in urban areas. To reduce racial disparities in survival, efforts directed at early detection and linkage to timely breast cancer treatment should be focused on black women living in the Low Country region of the state and in urban areas.

Citation Format: Oluwole Adeyemi Babatunde, Swann A. Adams, Jan M. Eberth, Tisha M. Felder, Robert Moran, Samantha Truman, Christian Alvarado, James Hebert. Identifying predictors of racial disparities in mortality among Blacks and Whites diagnosed with breast cancer in South Carolina [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4202.
Abstract 4203: Race and triple-negative breast cancer survival: A population-based study
Authors: Liu Ying , Lian Min , Colditz Graham A.
Published: August 2019

Tripe-negative breast cancer (TNBC) is characterized by lacking the expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, and thereby has poor prognosis. A higher incidence of TNBC in Black women than in White women has been well documented. However, it remains uncertain if there are racial differences in TNBC outcomes. Using the Surveillance, Epidemiology, and End Results dataset, we identified 23,077 women diagnosed with non-metastatic invasive TNBC, including 5,839 non-Hispanic Blacks and 17,238 non-Hispanic Whites, between 2010 and 2015. Cox proportional hazards regression was used to estimate relative risks (RRs) of breast cancer-specific death. During a median follow-up of 29 months, 2,494 cases died from breast cancer. The racial difference in estimated 5-year breast cancer-specific survival was 6.8% for younger (<65 years) women and 4.7% for older (≥65 years) women. The RR of breast cancer-specific death was 1.22 (95% CI 1.10-1.34) in Black women compared with White women after adjustment for age, insurance status, cancer registries, tumor characteristics, treatment, neighborhood socioeconomic deprivation, and rural locations. The race-associated higher risk was observed in women under 65 (RR=1.29, 95% CI 1.14-1.45), in less socioeconomically deprived counties (RR=1.33, 95% CI 1.18-1.49), and in urban counties (RR=1.27, 95% CI 1.15-1.41). The higher risk in Black women did not significantly vary by health insurance within age strata; the RR was 1.34 (95% CI 1.06-1.69) in younger patients having no insurance or Medicaid, 1.27 (95% CI 1.10-1.47) in younger patients having non-Medicaid insurance, 1.10 (95% CI 0.67-1.81) in older patients having no insurance or Medicaid, and 1.09 (95% CI 0.90-1.33) in older patients having non-Medicaid insurance. Black women with TNBC had worse survival compared with White counterparts, which was unlikely attributed to insurance coverage and was not evenly distributed across geographic areas. This warrants further research to investigate nonbiological and biological mechanisms for racial differences in TNBC outcomes, particularly in women under 65.

Citation Format: Ying Liu, Min Lian, Graham A. Colditz. Race and triple-negative breast cancer survival: A population-based study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4203.