Colón‐Otero, Gerardo

Abstract Background Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant neoplasm of the olfactory mucosa. Despite surgical resection combined with radiotherapy and adjuvant chemotherapy, ENB often relapses with rapid progression. Current multimodality, nontargeted therapy for relapsed ENB is of limited clinical benefit. Materials and Methods We queried whether comprehensive genomic profiling (CGP) of relapsed or refractory ENB can uncover genomic alterations (GA) that could identify potential targeted therapies for these patients. CGP was performed on formalin-fixed, paraffin-embedded sections from 41 consecutive clinical cases of ENBs using a hybrid-capture, adaptor ligation based next-generation sequencing assay to a mean coverage depth of 593X. The results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes (amplifications and homozygous deletions). Results Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in clinical trials. A total of 28 ENBs harbored GA, with a mean of 1.5 GA per sample. Approximately half of the ENBs (21, 51%) featured at least one CRGA, with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), with GA in PIK3CA, NF1, CDKN2A, and CDKN2C occurring in 7% of samples. Conclusion We report comprehensive genomic profiles for 41 ENB tumors. CGP revealed potential new therapeutic targets, including targetable GA in the mTOR, CDK and growth factor signaling pathways, highlighting the clinical value of genomic profiling in ENB.

Doxorubicin and the ERBB2 targeted therapy, trastuzumab, are routinely used in the treatment of HER2+ breast cancer. In mouse models, doxorubicin is known to cause cardiomyopathy and conditional cardiac knock out of Erbb2 results in dilated cardiomyopathy and increased sensitivity to doxorubicin-induced cell death. In humans, these drugs also result in cardiac phenotypes, but severity and reversibility is highly variable. We examined the association of decline in left ventricular ejection fraction (LVEF) at 15,204 single nucleotide polymorphisms (SNPs) spanning 72 cardiomyopathy genes, in 800 breast cancer patients who received doxorubicin and trastuzumab. For 7033 common SNPs (minor allele frequency (MAF) > 0.01) we performed single marker linear regression. For all SNPs, we performed gene-based testing with SNP-set (Sequence) Kernel Association Tests: SKAT, SKAT-O and SKAT-common/rare under rare variant non-burden; rare variant optimized burden and non-burden tests; and a combination of rare and common variants respectively. Single marker analyses identified seven missense variants in OBSCN (p = 0.0045–0.0009, MAF = 0.18–0.50) and two in TTN (both p = 0.04, MAF = 0.22). Gene-based rare variant analyses, SKAT and SKAT-O, performed very similarly (ILK, TCAP, DSC2, VCL, FXN, DSP and KCNQ1, p = 0.042–0.006). Gene-based tests of rare/common variants were significant at the nominal 5% level for OBSCN as well as TCAP, DSC2, VCL, NEXN, KCNJ2 and DMD (p = 0.044–0.008). Our results suggest that rare and common variants in OBSCN, as well as in other genes, could have modifying effects in cardiomyopathy.

AbstractHuman papillomavirus (HPV) vaccines offer primary prevention of cervical cancer and protection against other HPV‐associated cancers. HPV vaccine coverage in the United States (U.S.) remains low, particularly among older adolescents/young adults, and the uninsured. We assessed awareness and knowledge of HPV disease, HPV‐related cancers, and HPV vaccines among working, uninsured adults. Data from the 2014 Health Information National Trends Survey (HINTS 4, Cycle 4) were used as a benchmark. Patients were surveyed in late 2014 at the Volunteers in Medicine free clinic in Duval County, Florida. Surveys contained validated measures of HPV disease and vaccine knowledge; HPV‐related cancer knowledge was also assessed. Two‐hundred and ninety‐six surveys were analyzable with an 84% participation rate. Half (50.3%) of participants had heard of HPV, and 32.1% had heard of the HPV vaccine; in HINTS, these estimates were 63.6% and 62.7%, respectively (both P < 0.0001). In adjusted models, high HPV disease knowledge was associated with white race and increased education; high vaccine knowledge was associated with white race, increased education, and female sex. Recognition of HPV as a causative agent was 43.9% for cervical, 9.1% for anal, and 11.1% for throat cancers. For all HPV‐associated cancers, participants had lower knowledge/recognition relative to HINTS. The uninsured, socioeconomically disadvantaged adults we surveyed were unaware of a ubiquitous virus that can cause cancer and the existence of a vaccine to protect against it. These findings point to settings and populations in which initiatives to promote HPV vaccination as a cancer prevention tool remain critical.

Abstract Background/Purpose: Cancer registry data suggests that Duval County (greater Jacksonville, FL) has the highest breast cancer mortality rate for African American (AA) women in the southeastern US. Recent research revealed that race, residence, and insurance were associated with significantly poorer breast cancer outcomes in this area. Therefore we conducted a series of focus groups with AA breast cancer survivors from the urban core of Jacksonville, FL to directly address the disparities observed in our quantitative data. Methods: A series of focus groups were conducted to obtain qualitative data topics that included: breast cancer beliefs; delays to diagnosis and treatment; disparities; and health behaviors. Results: A total of 56 AA breast cancer survivors living in the urban core, with either Medicaid or who were uninsured, participated in the focus groups. Mean age was 62 years, with an average of 3.4 years since diagnosis. Only 21% of women were employed. Participants reported their mean time to see a doctor initially for their breast cancer was 39 days, and mean time to first treatment was 178 days. Participants responded that fear, financial limitations, and personal beliefs played the biggest roles in delays to diagnosis and treatment. Participants responded that poor health behaviors, genetics, lack of education, and personal beliefs accounted for both causing breast cancer, and the disparities observed in breast cancer mortality, and felt that environmental factors from living in the urban core also contribute. Conclusions: Our findings highlight several areas for potential intervention to reduce disparities in breast cancer. Citation Format: Sarah Osian, Monica Albertie, David Monticalvo, Steven Ames, Laila Samiian, Gerardo Colon-Otero. Examining reasons for breast cancer disparities in African American women in Duval County, FL. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C06.

Abstract Background: Human papillomavirus (HPV) is a causative agent in cervical cancer as well as anal, oropharyngeal, penile, and vaginal/vulvar cancers. Licensed, effective HPV vaccines have been available in the U.S. since mid-2006 for females and late 2011 for males and are recommended up to age 26. Despite this, in 2014, only 39.7% of U.S. girls and 21.6% of boys 13 to 17 years of age completed the three-dose vaccine series. ‘Lack of knowledge’ was a primary reason cited among parents for not vaccinating their children. HPV vaccination rates are lower still among 19-26 year olds, particularly among the uninsured. We assessed awareness and knowledge of HPV disease, HPV-related cancers, and HPV vaccines among working, uninsured adults and used 2014 data from the Health Information National Trends Survey (HINTS cycle 4) as a national benchmark against which to compare our data. Methods: Self-administered surveys were offered to patients attending appointments at the Volunteers in Medicine (VIM) clinic in Jacksonville, FL between September 10, 2014 and October 24, 2014. VIM provides free primary care for working individuals without insurance living and/or working in Duval County. Patients were eligible to participate if they were at least 18 years of age, not in acute distress, and had not completed a survey during pilot-testing. Surveys were available in English and Spanish and contained a validated HPV knowledge measure assessing disease knowledge and vaccine knowledge. Additionally, HPV-related cancer knowledge was assessed: 5 HPV-related (cervical, anal, throat, penile, vaginal/vulvar) and 4 not currently known to be HPV-related (lung, breast, prostate, skin). High knowledge was defined as having a knowledge score in the upper quartile of positive values. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression to assess the association of demographic characteristics with having high knowledge of HPV, HPV vaccines, and HPV-related cancer. Additional models assessed individual cancers. During the study period 356 patients were eligible to participate; of these, 55 declined (84% participation rate). Of the 301 surveys, 5 surveys were excluded from analysis due to excessive missing data; a total of 296 surveys were analyzed. Results: 50.3% of participants (n=149) had heard of HPV, 37.2% (n=110) correctly indicated that HPV is sexually transmitted, and 32.1% (n=95) had heard of the HPV vaccine. In HINTS 4, these estimates were 63.6%, 44.0%, and 62.7%, respectively. In adjusted models, high HPV disease knowledge was associated with race (OR non-white = 0.39 (0.19, 0.78)) and education (OR &gt;high school = 2.34 (1.14, 4.84)) while high HPV vaccine knowledge was associated with race (OR non-white = 0.42 (0.21, 0.82)), education (OR &gt;high school = 5.04 (2.30, 11.06)), and sex (OR male = 0.34 (0.12, 0.94)). Of the HPV-related cancers, 43.9% answered correctly for cervical, 9.1% for anal, 11.1% for mouth/throat, 11.5% for penile, and 30.7% for vaginal/vulvar cancer. Males were less likely than females to know that HPV is a causative agent for cervical (OR=0.41 (0.22, 0.75)) and vaginal/vulvar cancers (OR=0.43 (0.22, 0.86)). Conclusion: Using estimates obtained in HINTS 4 as a benchmark, awareness and knowledge of HPV, HPV-related cancers, and HPV vaccines were low among working, uninsured adult patients. In addition to improving access to HPV vaccination (e.g. volunteer clinics), the findings demonstrate a need for strategies to educate medically underserved adults about HPV. Maximizing access to HPV vaccination, including catch-up vaccination for adults up to age 26 are consistent with the recommendations of the President's Cancer Panel, the American College of Obstetricians and Gynecologists, the American College of Physicians, and the Advisory Committee on Immunization Practices. Citation Format: Carmen Radecki Breitkopf, Lila Finney Rutten, Debra Jacobson, Patrick Wilson, Monica Albertie, Robert M. Jacobson, Gerardo Colon-Otero. Awareness and knowledge of HPV, HPV-related cancers, and HPV vaccines in a working, uninsured clinic population. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B91.

Abstract Background: It has been shown that t(14;18), a translocation involving IgH and BCL-2 genes that is present in over 80% of all cases of follicular lymphomas, is detectable in the peripheral blood of up to 52% of normal Caucasian patients from Germany and up to 16% of normal individuals from Japan (Yasukawa et al, Blood 2001). The fact that follicular lymphoma is one of the two most common lymphomas in the USA and Germany and much less common in Japan, demonstrates that this molecular alteration is perhaps an early event in the development of this malignancy which is not sufficient for its causation. There have not been any studies evaluating the prevalence of this translocation in healthy African American (AA) subjects. We speculated that the prevalence of this translocation will be lower in healthy AA subjects given the findings of lower prevalence of IgH translocations in AA patients with multiple myeloma compared with Caucasian patients, which may explain the better outcome of myeloma in AA subjects (Baker et al, Blood 2013). This effort to evaluate the prevalence of t (14; 18) in AA subjects, was part of a pilot study in which we brought an educational program on the importance of cancer research together with concomitant access to a translational research project to AA churches utilizing a mobile research unit in an attempt to overcome some of the known barriers to AA subject participation in clinical research (Colon-Otero et al, Cancer2008; Colon-Otero et al, J Cancer Educ 2012). Methods: IRB approval of the project was obtained and peripheral blood samples collected from consented subjects during educational sessions in Northeast Florida AA Churches. Caucasian subjects were identified from the Mayo Clinic Bio-bank. DNA was isolated from the buffy coat fractions and a PCR quality control assay targeting a 293bp fragment of an HLA class II gene was used to determine acceptable DNA quality and quantity. Next, a two-step semi-nested PCR was performed on the t (14;18) major and minor breakpoint cluster regions using ~500ng of DNA for each assay. A consensus JH primer was used in combination with primers complementary to BCL-2 sequences for both, the major and minor breakpoint cluster regions. PCR products were run on a 1% agarose gel. In order to confirm the positive results, positive PCR products were analyzed by direct sequence by Sanger method and subsequently assembled to the human genome using BLAST tool. Results: A total of 110 blood samples from AA subjects were analyzed for the presence of t (14;18). A total of 13 of the samples were positive for the major breakpoint site (12%) and 4 were positive for the minor breakpoint site (4%), for a total of 17 positive samples (15%). In 167 Caucasian patients samples, a total of 22 (13%) were positive for the major breakpoint site and 5 (3%) were positive for the minor breakpoint site for a total of 27 positive samples (16%). All cases were confirmed by Sanger sequencing. Conclusions: The prevalence of t(14;18) is not significantly different among African American and Caucasian subjects from the USA based on our findings. This represents the first report of the prevalence of t(14;18) in an African American population. The prevalence found in our Caucasian subjects is significantly lower than what had been described in previous population series. A plausible explanation is the high heterogeneity of approaches used across studies, significantly affecting the assay sensitivity. Additional studies with larger series may reveal minor differences in the prevalence of t(14;18) among these populations. Citation Format: Scott Van Wier, Gerardo Colon-Otero, Gregory Ahmann, Esteban Braggio, Monica Albertie, Sikander Ailawadhi, Rafael Fonseca. Similar prevalence of t(14,18) in African American and Caucasian subjects. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B48.

Abstract There is a paucity of data on African Americans in community-based research secondary to difficulties in recruitment. These challenges include transportation, outreach barriers, fear and mistrust of researchers, lack of knowledge about disorder/issue under study, and lack of incentives. We hypothesized that we could improve recruitment in rural African American women by engaging community centers such as churches, community health centers, and doctor's offices. Over a 1 month period, we sought to recruit 40 women for a community based research project with a primary outcome of increasing activity in rural African American women (45-70 years old) with knee pain. The outlets used to recruit these women included: five churches with a community liaison, many primary care physicians' offices, and a newspaper ad. In 1 month, 67 women expressed interest in our program by initiating contact. Of those 67 women, 42 were eligible and 37 were enrolled. Of the 42 eligible women, 24 were recruited from churches, 11 through word of mouth, 3 from physicians' offices, and 3 from the newspaper ad. Lack of literature on how to recruit in rural African American communities is a significant barrier to research participation among African Americans. In this project, we provide a reproducible recruitment process for engaging rural African American women in community based research. While our primary focus was knee pain, this recruitment process can easily be translated into other areas of community based research including cancer and cardiovascular disease among others. Citation Format: Michelle Scott, Tamara Huff, Monica Albertie, Gerardo Colon-Otero. Recruitment methods for engaging rural African American populations in community-based research. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A27.

Abstract DMOT4039A, a humanized anti-mesothelin mAb conjugated to the antimitotic agent monomethyl auristatin E (MMAE), was given to patients with pancreatic and ovarian cancer every 3 weeks (0.2–2.8 mg/kg; q3w) or weekly (0.8–1.2 mg/kg). A 3+3 design was used for dose escalation followed by expansion at the recommended phase II dose (RP2D) to evaluate safety and pharmacokinetics. Antitumor response was evaluated per RECIST 1.1 and serum CA19-9 or CA125 declines. Tumor mesothelin expression was determined by IHC. Seventy-one patients (40 pancreatic cancer; 31 ovarian cancer) were treated with DMOT4039A. For the q3w schedule (n = 54), the MTD and RP2D was 2.4 mg/kg, with dose-limiting toxicities of grade 3 hyperglycemia and grade 3 hypophosphatemia at 2.8 mg/kg. For the weekly schedule (n = 17), the maximum assessed dose was 1.2 mg/kg, with further dose escalations deferred because of toxicities limiting scheduled retreatment in later cycles, and therefore the RP2D level for the weekly regimen was determined to be 1 mg/kg. Across both schedules, the most common toxicities were gastrointestinal and constitutional. Treatment-related serious adverse events occurred in 6 patients; 4 patients continued treatment following dose reductions. Drug exposure as measured by antibody-conjugated MMAE and total antibody was generally dose proportional over all dose levels on both schedules. A total of 6 patients had confirmed partial responses (4 ovarian; 2 pancreatic) with DMOT4039A at 2.4 to 2.8 mg/kg i.v. q3w. DMOT4039A administered at doses up to 2.4 mg/kg q3w and 1.0 mg/kg weekly has a tolerable safety profile and antitumor activity in both pancreatic and ovarian cancer. Mol Cancer Ther; 15(3); 439–47. ©2016 AACR.

BACKGROUNDNational Cancer Institute (NCI)/National Comprehensive Cancer Network (NCCN)–designated cancer centers (CCs) offer patients state‐of‐the‐art treatment, but their impact on multiple myeloma (MM) patient outcomes has not been evaluated.METHODSAdult MM patients diagnosed between 1973 and 2011 were identified from the Surveillance, Epidemiology, and End Results database and were stratified by the county of residence at the time of diagnosis and the year of CC designation. The influence of NCI/NCCN CC access, race, and the year of diagnosis on overall survival (OS) was evaluated with a Cox regression model.RESULTSA statistically significant OS improvement was noted in patients diagnosed after 1995 with access to 2 or more NCI CCs overall (P = .002 for 1996‐2002; P < .001 for 2003‐2011) and by race for whites (hazard ratio [HR] for 1996‐2002, 0.85; 95% confidence interval [CI], 0.78‐0.91; HR for 2003‐2011, 0.85; 95% CI, 0.79‐0.91) but not for nonwhites. For NCCN access, improvement was seen in 1996‐2002 (P = .003), in 2003‐2011 (P < .001), and by race for whites (HR, 0.917; 95% CI, 0.88‐0.95) and nonwhites (0.94; 95% CI, 0.89‐0.99), but within nonwhites, this was true only for African Americans (AAs; HR, 0.88; 95% CI, 0.81‐0.97) and not for Asians, Hispanics, or Native Americans.CONCLUSIONSImprovement in OS was seen in MM patients diagnosed after 1995 with access to 1 NCCN CC or 2 or more NCI CCs. NCI access benefited only whites, whereas NCCN access benefited only white and AA patients. No OS benefit was seen for any subgroup with access to only 1 NCI center. Eliminating racial disparities in health care access and utilization is needed to improve outcomes. Cancer 2016;122:618–625. © 2015 American Cancer Society.