Personalized Cancer Research Articles

Abstract P6-09-04: Volumetric breast density improves breast cancer risk prediction

Abstract Introduction: There is increasing interest in implementing personalized breast cancer screening strategies rather than relying on population based guidelines. Most risk models do not include breast density and two models that do rely on subjective BI-RADS categories; all have limited discriminatory ability (C-statistics ranging from 0.60-0.74). Our aim was to develop a model that includes an automated objective and numeric volumetric measurement of breast density with other known risk factors to improve risk prediction. Methods: A case-control study design was used to evaluate the association between risk factors and breast cancer diagnosis. All women diagnosed with breast cancer during 2003-13 with a digital contralateral mammogram at the University of Virginia at the time of diagnosis were eligible as cases. All women without a breast cancer diagnosis but with a digital mammogram at UVA during 2003-2008 were eligible as controls. Risk factor information was collected using a self-reported electronic questionnaire. Mean automated volumetric breast density (Volpara, NZ) was calculated for each patient as a percentage. Controls were matched to cases in a 2:1 ratio based on age group, race, and education, using the GREEDY algorithm. Case-control selections were made using the weighted sum of the absolute differences between the case and control matching factors. Conditional logistic regression using the partial likelihood function from Cox proportional hazard’s regression was used to fit risk prediction equations to the matched case-control study dataset, with stratification for each case matched set. A full model was estimated including all available covariates for use as a model performance reference standard. A reduced model was then estimated including covariates in the full model that had a Wald Chi-Square/degrees of freedom ratio > 1.0. The performance of the full and reduced models was measured using the C index and the maximum R-Square statistic. Results: The study enrolled 3,445 women; 839 cases and 2,606 controls. Multivariable analysis was conducted using 825 cases and 1,628 controls with 1 or more breast studies reported for the surveyed population. The matching process yielded balanced matching factor values between cases and controls, with no significant differences in age group (p = 0.95), race (p = 0.13), or education (p = 0.86). The full prediction model (with 97 df) yielded a C index of 0.88, and an R-Square of 0.53. The reduced model (with 15 df) had a C index of 0.83 and an R-Square of 0.54. Variables in the reduced model included: mean breast density; biopsy showing ADH, ALH/LCIS; BMI; use of HRT, contraceptives, NSAIDS; smoking; exercise; parity; diabetes; family history of breast cancer, HBOC, Li-Fraumeni, or Cowden Syndromes and/or BRCA mutation. Mean volumetric breast density was a leading independent predictor of case status in both the full (p<0.0001) and reduced models (p=0.0212). Conclusion: Volumetric breast density with other known risk factors may provide more accurate individual risk assessment, enabling clinicians to develop patient centered risk based screening protocols that better inform decision making while including patient preferences. The next steps require independent validation of the risk model in other populations. Citation Format: Jennifer A Harvey, George J Stukenborg, Wendy F Cohn, Kathy L Repich, Olivier Alonzo, Wendy M Novicoff, Martin D Yaffe, William A Knaus. Volumetric breast density improves breast cancer risk prediction [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-09-04.

Abstract PR12: Directing personalized breast cancer treatment with pathway signatures

Abstract One of the major limitations in the treatment of breast cancer is the patient to patient heterogeneity of the tumors. This is evidenced by the well-known intrinsic subtypes of breast cancer, including luminal A and B, basal, claudin-low, HER2+ and normal like. If one considers the hormonal status (ER / PR) of the breast cancers in addition to the intrinsic subtypes, then additional classifications are apparent. Indeed, recent work has suggested that there are approximately 17 subtypes of breast cancer. With these various types of breast cancer, clinicians are faced with the challenge of determining the optimal treatment strategy for the individual breast cancer patient. When treatment options are considered in this way, it becomes readily apparent that breast cancer, and cancer in general, needs to be treated with a personalized approach. We believe that one mechanism to address the requirement for personalized therapy is to employ cell signaling pathway signatures based on gene expression data to differentiate the tumors into treatment groups. As a proof of principle experiment, we have used pathway signatures in a mouse model of breast cancer. An extensive gene expression database was constructed for 23 major mouse models of breast cancer encompassing over 1100 breast cancer samples. Predictions for key signaling pathway activation were calculated using genomic data and pathway signatures. This dataset demonstrated heterogeneity in the vast majority of mouse model systems with important relations to human breast cancer. Analysis of this data prompted a focus on the MMTV-Myc model as the genomic signatures clearly predicted various subtypes of cancer in the MMTV-Myc model system. Indeed, in one subtype of breast cancer in the Myc model we noted elevation of the EGFR, TNF and Ras pathways whereas these pathways are not predicted to be active in a second subtype of cancer from the same model system. In the second tumor subtype, there is a high predicted activity for other pathways, including Myc, Stat3 and AKT. To demonstrate that these predictive signatures can be used to guide clinical therapy, we then took an approach where we targeted each of the pathways in a combinatorial approach with small molecule inhibitors in transplantable tumors from the initial tumor subtypes. Thus, we have two therapies, each tailored to a specific subtype of a mouse model breast cancer. Safety trials for both weight and liver enzymes for the combination of the three drugs in each treatment arm revealed that there were no significant side effects when inhibitors were used at the low doses designed for use in therapy. Importantly, we have shown that the predicted combination therapy is effective in blocking tumor growth in the tumor type that is predicted to be responsive while it is ineffective in blocking tumor growth in the other subtype of tumors. These results clearly demonstrate in a proof of principle experiment that using pathway signatures is a viable mechanism for identifying and directing treatment for breast cancer. This abstract is also presented as Poster A02. Citation Format: Jing-Ru Jhan, Daniel Hollern, Eran R. Andrechek. Directing personalized breast cancer treatment with pathway signatures. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr PR12.

Abstract A44: Directing personalized breast cancer treatment with pathway signatures

Abstract One of the major limitations in the treatment of breast cancer is the patient to patient heterogeneity of the tumors. This is evidenced by the well-known intrinsic subtypes of breast cancer, including luminal A and B, basal, claudin-low, HER2 and normal like. If one considers the hormonal status (ER / PR) of the breast cancers in addition to the intrinsic subtypes, then additional classifications are apparent. Indeed, recent work has suggested that there are approximately 17 subtypes of breast cancer. With these various types of breast cancer, clinicians are faced with the challenge of determining the optimal treatment strategy for the individual breast cancer patient. When treatment options are considered in this way, it becomes readily apparent that breast cancer, and cancer in general, needs to be treated with a personalized approach. We believe that one mechanism to address the requirement for personalized therapy is to employ cell signaling pathway signatures to differentiate the tumors into treatment groups. As a proof of principle experiment, we have used pathway signatures in a mouse model of breast cancer. The signatures clearly predict various subtypes of cancer in the MMTV-Myc model system with elevation of the EGFR, TNF and Ras pathway in one subtype of tumor whereas these pathways are not predicted to be active in a second subtype of cancer from the same model system. In the second tumor subtype, there is a high predicted activity for other pathways, including Myc, Stat3 and AKT. To demonstrate that these predictive signatures can be used to guide clinical therapy, we then took an approach where we targeted each of the pathways in a combinatorial approach with small molecule inhibitors in transplantable tumors from the initial tumor subtypes. Thus, we have two therapies, each tailored to a specific subtype of a mouse model breast cancer. Safety trials for the combination of the three drugs in each treatment arm revealed that there were no significant side effects when inhibitors were used at the low doses designed for use in therapy. Importantly, we have shown that the predicted combination therapy is effective in blocking tumor growth in the tumor type that is predicted to be responsive while it is ineffective in blocking tumor growth in the other subtype of tumors. These results clearly demonstrate in a proof of principle experiment that using pathway signatures is a viable mechanism for identifying and directing treatment for breast cancer. Citation Format: Jing-Ru Jhan, Eran Andrechek. Directing personalized breast cancer treatment with pathway signatures. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A44.

Abstract SS03-03: The promise and the challenge of personalized medicine: A patient advocate perspective

Abstract This Special Session, “Personalized Medicine: Promise and Pitfalls,” is a direct outcome of a process that began in late 2012 as the first initiative of The Pathways Project, a radically inclusive organization that creates communities and catalyzes movements that put people at the center of health care research and delivery. The Pathways directors wrote and posted “Personalized Medicine and Cancer Health Disparities—A Discussion Paper” (http://pathways-project.org/wp-content/uploads/2012/11/Patient-Voices-11-15.pdf) on the Patient Voices section of the Pathways webpage as a prelude to convening online Think Tank sessions to enhance awareness of and stimulate dialogue and action on these critical issues. The discussion paper—drafted as a starting point for more thorough investigation and reflection—and this presentation seek to focus the dialogue, pose necessary questions, obtain more than cursory acknowledgment, and engage diverse segments of the population (with patients at center) in considering and acting on the contradictions and challenges embedded within the promise of personalized medicine, especially for medically underserved populations. Extracting from the discussion paper, Think Tank deliberations, and experience in numerous patient communities, this segment of the session • Focuses on a patient advocate perspective and concerns • Highlights critical linking issues • Covers the great promise of and the daunting challenges related to actualizing the concept of “the right treatment to the right patient at the right time” • Proffers the idea that given the discordance of research and access—that is, the fact that as significant public research dollars are used to fund research on personalized medicine, large portions of the population cannot even access standard care—the emphasis on personalized medicine might be viewed as public funding of private access and might widen the gap in health equity and outcomes To consider the implications of personalized medicine across populations and levels of access to care and to lay the groundwork for meaningful, candid dialogue, broad definitions are offered for terms such as cancer health disparities, personalized health care, and standard of care. And then, a series of questions are posed to focus the discussion on substantive review of the implications and realities of personalized medicine across populations and disciplines, with the hope that the challenges will not overtake the promise and exacerbate the already unacceptable state of cancer (and other) health disparities. Questions include the following: • Will personalized medicine reach populations historically and currently poorly served by standard treatment regimens? If so, what is currently in place to enhance the likelihood? • As we work to do away with race as a biological proxy for disease risk, management, and treatment, how do we act to eliminate social inequities, which prevent the delivery of the great promise—the right treatment to the right patient at the right time? • What must we do to move beyond race as a first filter? • How do we move from health access and care controlled by social determinants to personalized medicine for all? • If we do not eliminate barriers to gateway processes or mechanisms (such as clinical trial participation and specimen banking), at what cost do we proceed in funding and in otherwise focusing resources on research that will yield health care and outcomes available only to some? • Can funding of personalized medicine research enhance the likelihood of good, or improved, outcomes for some—making such research/funding a private matter—at the expense of those already disadvantaged—making it a public health issue? • Is it likely that as research makes personalized treatment advances possible, the gap between those with access to advances and those without will be widened? Given these concerns and the possibility of unintended “harm,” that is, exacerbation of the current imbalance in access, care, and outcomes, these questions must be asked and vigorously debated. And, the frank, unfiltered responses should form the bases of action, without which a widening gap is a likely unintended outcome. Personalized medicine and cancer health disparities, often studied and covered separately, are fundamentally linked, and without focused attention, considerable patient input and engagement, and enhanced public awareness and understanding of the issues and intersections, the realization of personalized medicine and health care may present one of the critical public health and social justice issues of our time. The ultimate question is, how do we proceed with rapid research and implementation of personalized medicine and equally rapid elimination of cancer health disparities? This important discussion—focused and framed on specific critical issues and questions—must move from casual conversation and head-shake acknowledgments to clear and direct action steps and interventions. Citation Format: Mary Jackson Scroggins. The promise and the challenge of personalized medicine: A patient advocate perspective. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr SS03-03. doi:10.1158/1538-7755.DISP13-SS03-03

Challenges in the detection, prevention, and treatment of HIV-associated malignancies in low- and middle-income countries in Africa.

Cancers associated with immunosuppression and infections have long been recognized as a major complication of HIV/AIDS. More recently, persons living with HIV are increasingly diagnosed with a wider spectrum of HIV-associated malignancies (HIVAM) as they live longer on combination antiretroviral therapy. This has spurred research to characterize the epidemiology and determine the optimal management of HIVAM with a focus on low-and middle-income countries (LMICs). Given background coinfections, environmental exposures, host genetic profiles, antiretroviral therapy usage, and varying capacities for early diagnosis and treatment, one can expect the biology of cancers in HIV-infected persons in LMICs to have a significant impact on chronic HIV care, as is now the case in high-income countries. Thus, new strategies must be developed to effectively prevent, diagnose, and treat HIVAM in LMICs; provide physical/clinical infrastructures; train the cancer and HIV workforce; and expand research capacity-particularly given the challenges posed by the limitations on available transportation and financial resources and the population's general rural concentration. Opportunities exist to extend resources supported by the President's Emergency Plan for AIDS Relief and the Global Fund to Fight AIDS, Tuberculosis, and Malaria to improve the health-care infrastructure and train the personnel required to prevent and manage cancers in persons living with HIV. These HIV chronic care infrastructures could also serve cancer patients regardless of their HIV status, facilitating long-term care and treatment for persons who do not live near cancer centers, so that they receive the same degree of care as those receiving chronic HIV care today.

Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go?

Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go?

Sa1417 Impact of Socioeconomic Status on Bowel Preparation Quality and Adenoma Detection Rate in a Safely Net Hospital

The effectiveness of screening colonoscopy programs depends on adequate bowel preparation quality and appropriate adenoma detection rates. Lower socioeconomic status (SES), as measured by insurance status, has been suggested as a predictor of suboptimal bowel preparation. Higher rates of suboptimal bowel preparation in low SES patients may prevent endoscopists from achieving recommended adenoma detection rate (ADR) benchmarks, limit the effectiveness of colon cancer screening programs, and increase the burden of colorectal cancer in persons of lower SES.

Cell proliferation and tissue remodeling are major determinants of cancer metabolism and the response to drugs targeting metabolism

Background Alterations in cell proliferation and tissue remodeling are major hallmarks of cancer. Given that these two physiological processes require a significant investment of metabolic resources, we hypothesize that the metabolism of cancer cells is, in a first approximation, determined by the magnitude of cell proliferation and tissue remodeling. Materials and methods To address this question in further detail we have analyzed in vitro data characterizing cancer cell lines and gene expression profiles of human cancers. Results We show that the metabolism of cancer cells is strongly correlated with cell proliferation and tissue remodeling. Based on in vitro data, cancer cell lines align from an extreme of highly proliferating cells of relatively small size to another extreme of slowly proliferating cells with large size and mesenchymal properties [1]. Similarly, in human cancers we detect a strong negative correlation between gene signatures associated with cell proliferation and tissue remodeling [2]. The stratification of human cancers based on the cell-proliferation/ tissue-remodeling signatures results in divergence in the survival plots as significant as those obtained using current site-specific classifications. Furthermore, in vitro data suggest that these different subtypes have a differential sensitivity to diverse drug classes targeting metabolism [1]. Conclusions We conclude that human cancers can be subject to a universal cell-proliferation/tissue-remodeling classification independent of their site of origin that can guide personalized treatment targeting cancer metabolism.

Modified nucleosides as biomarkers for early cancer diagnose in exposed populations

There is increasing worldwide interest in developing of markers for tumor diagnosis and identification of individuals who are at high cancer risk. Cancer, like other diseases accompanied by metabolic disorders, causes characteristic effects on cell turnover rate, activity of modifying enzymes, and RNA/DNA modifications. This results in an increased excretion of modified nucleosides in cancer patients. Therefore, for many years modified nucleosides have been suggested as tumor markers. The aim of the study was to elucidate further the usefulness of urinary nucleosides as possible markers at early detection of cancer in persons which are exposed against tumor promoting influences during their working life. Uranium miners are exposed to many kinds of pollutants that can cause health damage even lead to carcinogenesis. We analyzed modified nucleosides in urine samples from 92 miners who are at high risk for lung cancer to assess the levels of nucleosides by a multilayer perceptron (MLP) classifier - a neural network model. Eighteen nucleosides/metabolites were detected with reversed-phase high-pressure liquid chromatography (RP-HPLC). A valid set of urinary metabolites were selected and multivariate statistical technique of multilayer perceptron neural network were applied. In a previous study, MLP shows a sensitivity and specificity of 97 and 85%, respectively. MLP classification including the most relevant markers/nucleosides clearly demonstrates the elevation of RNA metabolism in miners, which is associated with possible malignant disease. We found that there were 30 subjects with early health disorders among 92 uranium workers based on MLP technique using modified nucleosides. The combination of RP-HPLC analysis of modified nucleosides and subsequent MLP analyses represents a promising tool for the development of a non-invasive prediction system and may assist in developing management and surveillance procedures.

Abstract P2-12-06: Implementing a comprehensive genetic risk assessment and testing service at an outpatient breast imaging center

Abstract Breast cancer is the most common cancer in women, and there are a variety of available methods to determine which women have an above-average risk to develop breast cancer. However, it can be a challenge to identify patients who may benefit from genetic counseling and should be offered genetic testing. This study examines our data and experience in performing genetic risk assessment and offering on-site genetic counseling in an outpatient breast imaging center. A screening questionnaire asking about personal and family cancer history was created and given to every patient coming in for either screening or diagnostic mammogram. The questionnaires were reviewed by both the breast radiologist and nurse navigator, and those identified as appropriate were offered appointments with the genetic counselor. Genetic counseling appointments are available two days per month. Data was obtained over an eight month period from August 2012- March 2013. During this time, 8768 mammograms were performed and 406 individuals were identified as having a history suspicious for hereditary breast and ovarian cancer and offered an appointment with a genetic counselor. Out of these 406 individuals, 83 scheduled appointments with the genetic counselor, 108 declined appointments, and 215 are pending. Some of the genetic counseling appointments were made after March 31, 2013 and the outcomes are not included at this time. Thirty-six patients were ultimately seen for genetic counseling and risk assessment in this time frame, with 28 undergoing testing. Out of the 28 patients tested during this time period, one was positive and one had a variant of unknown significance. Out of the 36 patients seen for genetic counseling, 27 were identified as increased risk for breast cancer either by having a Gail risk assessment score ≥1.67% or Tyrer-Cuzick risk assessment score ≥19.5% and were eligible for chemoprevention or breast MRI, respectively. This clinic model demonstrates that on-site genetic counseling is feasible in an outpatient breast imaging setting. Prior to offering on-site genetic counseling, this center used the same questionnaire to identify patients and sent a recommendation for genetic counseling to the referring physician ordering the mammogram. This system relied on the physician to make a referral to an off-site genetic counselor. From the period of May 2012- August 2012, 139 patients were identified by the same questionnaire with 17 patients being referred to genetic counseling, and only 3 of these patients were ultimately seen by the genetic counselor. By providing on-site genetic counseling, the percentage of patients seen for genetic counseling increased from 2.15% (3/139) to 8.87% (36/406). In addition, more outcomes are known since 100% of patients identified to be at risk for Hereditary Breast and Ovarian cancer were offered genetic counseling, and if a patient declined, a reason was documented. The risk assessment algorithm outlined here identified more patients that either tested positive for a BRCA mutation or were at an increased 5-year or lifetime risk to develop breast cancer that may not have been detected otherwise. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-12-06.

Quantum Dots For Diagnosis Of Cancers

The most widely researched and investigated disease, both medically and scientifically, in the current era is the formidable disease cancer. The chances of successful treatment and hence the curability increases if it is diagnosed at an early stage. This can be done only by increasing awareness amongst people about its early diagnosis and screening tests. Cancer screening exams refers to the medical tests to identify people who have disease, often before symptoms of the illness occur. These tests help detecting cancer at its earliest stage when the chances for curing the disease are greatest. Advancements in nanotechnology have made the early screening of cancer possible. In this review, we have discussed the developments in nanotechnology that have encouraged the more recent innovative solutions for early diagnosis and treatment of cancer. Quantum dots, nanometer-sized semiconductors, are the new class of novel biosensors, now being exclusively employed as alternative fluorescent probes due to their unique properties, such as intense and stable fluorescence for a longer time, resistance to photobleaching, large molar extinction coefficients, and highly sensitive detection, due to their ability to absorb and emit light very efficiently. Their size approximates that of individual biomolecules, which offers unique possibilities for the ultrasensitive detection of cancer in persons’ serum, tissues, and other body fluids, when tagged with specific antibodies against specific tumor markers. In this review, we have account briefly the applications of semiconductor QDs employed for the early screening and diagnosis of cancer biomarkers between the years 2009-2012. We believe that this review will enable workers in the field to devise new applications of these materials for the early detection of cancer, and ultimate reduction in incidence of the disease. Copyright © 2013 VBRI press.

Abstract A49: GSTM1, GSTT1, GST polymorphisms, physical activity, and breast cancer risk in premenopausal women of European ancestry

Abstract Background: Susceptibility to premenopausal breast cancer may in part be attributable to inter-individual variability in GST genetic polymorphisms and lifestyle risk factors. Glutathione S-transferase (GST), a family of Phase II detoxification enzymes, may play an important role in breast cancer risk. GSTs are protective through their defense against free radicals and detoxification of toxic compounds, but may also participate in the activation of oxidative metabolites of carcinogenic compounds. Studies have postulated increased susceptibility to cancer in persons with GSTMI or GSTT1 deletions polymorphisms. In particular, inherited homozygous deletions of the GSTM1 and GSTT1 genotype can lead to the absence of enzyme activity, which is associated with increased breast cancer risk. Leisure time physical activity is associated with decreased breast cancer risk any may attenuate oxidative damage in subjects with GSTM1 and GSTT1 deletion genotypes. Hence, physical activity may protect against breast cancer through interaction with specific GST genotypes. We investigated associations between (1) GSTM1 and GSTT1 deletion genes, GST SNPs and premenopausal breast cancer risk; and (2) whether interactions between GST genotype and leisure time physical activity influenced breast cancer risk in women of European Ancestry. Methods: The study design is a population-base case-control study (1476 cases and 699 controls) of premenopausal women (<50 years of age). Study participants were first primary breast cancer cases and unaffected population-based controls recruited through three population-based registries from the Breast Cancer Family Registry. Clinical and epidemiologic data were taken from standardized family history and epidemiology questionnaires. The physical activity questionnaire provided data on the number of hours per week of leisure time exercise during specific age periods through-out life. Lifetime and recent (previous 3 years) physical activity was calculated using a previously described algorithm, which assigned 5.4 and 8.5 METs to moderate and strenuous activities, respectively, and corrected for demographic characteristics affecting MET value of activity. GSTM1 and GSTT1 deletion genes and 14 GST single nucleotide polymorphisms (SNP) were genotyped using TaqMan™real-time PCR technology. Logistic regression analysis was used to estimate odds ratios and corresponding 95% confidence intervals (CI) for associations between premenopausal breast cancer and GST deletion genotypes, GST SNPs and interactions by physical activity. Results: We did not find robust statistically significant associations between the GST deletion genes, GST SNPS and physical activity with premenopausal breast cancer risk. After adjustment, GSTM3 SNP rs1332018 was nominally associated with the ER+/PR+ breast cancer subtype (p<0.05). We found nominally significant interactions between two linked SNPs in the GSTM3 gene, rs7483 (a nonsynonymous SNP) and rs1537234, and level of recent physical activity for women with the ER-/PR- subtype (p<0.01), after adjusting for known risk factors. However these associations were not significant after Bonferroni correction. Conclusion: The observed associations between established GST deletion genotypes, GST SNPs and premenopausal breast cancer in women of European ancestry were not significant after accounting for multiple comparisons. However, results suggest that risk for ER-/PR- premenopausal breast cancer may change depending on level of physical activity in women with one or more GST risk alleles. Given the potential for public health impact, these results support a need for replication studies to confirm or refute these associations. Citation Format: Tanya Agurs-Collins, Edwin S. Iversen, Frank Perna, Bolormaa Baljinnyam. GSTM1, GSTT1, GST polymorphisms, physical activity, and breast cancer risk in premenopausal women of European ancestry. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A49.

Women's understanding of personal breast cancer risk: Does ethnicity matter?

4 Background: A woman’s understanding of her breast cancer risk is an important precursor for care. A valid estimate allows for greater opportunity to consider early detection modalities and chemopreventive medications. The USPSTF recently encouraged women who have an increased risk of developing a first breast cancer and a low risk of side effects to take tamoxifen or raloxifen. The objective of this study is to compare patients' perceived breast cancer risk with their calculated risk and then parse those findings by ethnicity. Methods: Anonymous, IRB approved, pre-piloted questionnaires were filled out by women at 21 mammography centers on Long Island. The survey included questions about patient demographics, patient’s estimates of their own breast cancer risk and personal risk factors. Results: 9,873 respondents qualified for inclusion in our analysis. Women were asked to quantify their breast cancer risk by age 90. Overall, 707 (9.4%) were in line with their risks, 3,359 (44.7%) underestimated risk and 3,454 (45.9%) overestimated their risk. When parsed by ethnicity, of the 781 African Americans, 8.7% were in line, 57.6% underestimated risk, and 33.7% overestimated risk. Of the 245 Asians, 10.2% were in line, 58.8% underestimated risk, and 31% overestimated risk. Of the 427 Hispanics, 8.9% were in line, 50.4% underestimated risk, and 40.8% overestimated risk. Of the 6850 Caucasians, only 10.2% were in line, 38.6% underestimated risk, and 51.3% overestimated risk. Conclusions: Most women lack accurate knowledge of their own breast cancer risk – 90.6% overall. When parsed by ethnicity, while there was a statistical difference between groups, the difference was not important because overall understanding was very low. Caucasian women tended to overestimate their risk compared with other ethnic groups, possibly resulting in unnecessary anxiety. African American and Hispanics tended to underestimate risk compared with Caucasians, possibly resulting in underutilization of available resources. Patients must have a better understanding of their personal risk. Study findings should help refocus educational efforts because increased knowledge of breast cancer risk will enable providers to tailor an individual’s medical treatment plan.

101 Occupational exposure to tetrachloroethylene and the risk of bladder cancer: A meta-analysis

ObjectivesThe risk of bladder cancer in persons occupationally exposed to tetrachloroethylene was summarised using a meta-analysis.MethodsStudies were identified from a Pubmed literature search including the terms “drycleaner, dry-cleaning, occupation, tetrachloroethylene,...

Inverse occurrence of cancer and Alzheimer disease

To evaluate the incidence of cancer in persons with Alzheimer disease (AD) and the incidence of AD dementia in persons with cancer. This was a cohort study in Northern Italy on more than 1 million residents. Cancer incidence was derived from the local health authority (ASL-Mi1) tumor registry and AD dementia incidence from registries of drug prescriptions, hospitalizations, and payment exemptions. Expected cases of AD dementia were calculated by applying the age-, sex-, and calendar year-specific incidence rates observed in the whole population to the subgroup constituted of persons with newly diagnosed cancers during the observation period (2004-2009). The same calculations were carried out for cancers in patients with AD dementia. Separate analyses were carried out for the time period preceding or following the index diagnosis for survivors and nonsurvivors until the end of 2009 and for different types and sites of cancer. The risk of cancer in patients with AD dementia was halved, and the risk of AD dementia in patients with cancer was 35% reduced. This relationship was observed in almost all subgroup analyses, suggesting that some anticipated potential confounding factors did not significantly influence the results. The occurrence of both cancer and AD dementia increases exponentially with age, but with an inverse relationship; older persons with cancer have a reduced risk of AD dementia and vice versa. As AD dementia and cancer are negative hallmarks of aging and senescence, we suggest that AD dementia, cancer, and senescence could be manifestations of a unique phenomenon related to human aging.

The first 10 years experience with genetic testing (GT) for BRCA1/2 mutations in a publicly funded program at a tertiary care teaching hospital in Ontario, Canada.

1550 Background: Publicly funded testing for BRCA1/2 mutations in Ontario has been available for high-risk individuals since 2000. The criteria are based on personal and/or family cancer history and ethnicity. We reviewed the results of the first 10 yrs of testing at our institution, a regional cancer centre in an academic, tertiary care teaching hospital. Methods: This REB-approved, retrospective study included individuals who had GT from 2001-2011. Sociodemographic, clinical, and GT results were collected. Results: 2,305 individuals met criteria and underwent GT between Jan. 2001and Dec. 2011. Of all tested subjects, 93% were female, median age was 55 yrs., 23% were of Ashkenazi Jewish (AJ) ancestry and 80% lived in an area with family income $50-100K/yr. BRCA1/2 mutations were present in 16%, 8% had unclassified variant (UCV), 76% had normal sequence. We excluded 460 individuals who had predictive GT for a familial mutation, and results are shown in the Table. For each carrier, an average of four additional relatives had GT. The most common criteria for GT was at least three cases of ovarian or breast cancer at any age on the same side of the family. BRCA mutations were most common among those AJ, Italian, Asian Oriental and English ancestry. Wait time for GT result improved from 107 wks. in 2001 to 8 wks. in 2011. Conclusions: In our tested population, the prevalenceof BRCA1/2 mutations was high. Over time wait times improved and more relatives were tested. [Table: see text]

Cancer risks and mutation spectrum of mismatch repair genes in African American families with Lynch syndrome.

1530 Background: Although African Americans (AA) have the highest colorectal cancer (CRC) incidence and mortality of all populations in the United States, no studies have determined cancer risk and mismatch repair (MMR) genes mutation spectrum in LS patients of AA ancestry and the contribution of this syndrome to cancer disparities. Thus, the aims of this study are: (1) to describe LS cancers in AAs; (2) to investigate the mismatch repair (MMR) gene mutation spectrum in AA families with LS; (3) to determine how Amsterdam II criteria, revised Bethesda guideline, and PREMM(1,2,6) model perform for predicting MMR gene mutations in this population. Methods: Pedigrees of AA families with deleterious mutation or suspected deleterious mutation in MMR genes from five US referral centers were analyzed for personal and familial clinical cancer histories. Results: Twenty-four AA families were identified, of which 22 had deleterious mutations (15 MLH1, 4 MSH2, 2 MSH6, 1 PMS2) and 2 had suspected deleterious mutations (1 MLH1, 1 MSH2). Three recurrent mutation were found in MLH1(677G>A, IVS1-2A>G, IVS4-1G>A), accounting for 25% of all mutations. Of 24 probands, 58% were female and 96% had personal history of cancer. The median age at first primary tumor was 42yrs (range 28-57) and 50% developed more than 1 primary tumor. The majority of probands (79%) had CRC (median age of onset – 42yrs [range 31-61]), of which 26% had at least 2 CRC primaries. Endometrial cancer developed in 50% of the women (median age of onset – 51yrs [range 32-57]). Amsterdam II and Bethesda criteria were met in 63% and 88% of the individuals, respectively. Median score by PREMM(1,2,6) model was 54% (range 12.9-99.8). Conclusions: To our knowledge, this is the largest series of AA families with LS reported to date. Earlier age of onset for CRC at 42yrs (previously reported ~45 yrs) is suggested. The majority of mutations were found in MLH1 (67%), including three recurrent mutations. A 10% cutoff for PREMM(1,2,6) predictive model identified all mutation carriers. Larger studies are warranted to confirm the differences observed in age of CRC onset in this population.

Do lifestyle factors influence colorectal cancer risk in Lynch syndrome?

Lynch syndrome (LS) is one of the inherited colorectal cancer (CRC) syndromes and is due to germline mutations in one of the mismatch repair (MMR) genes. Within LS affected-families the expression of the syndrome varies, which suggests that other factors, such as lifestyle factors, have an influence on the LS phenotype. This review gives an overview of studies that assessed the role of lifestyle factors in the development of CRC in LS. Several published studies investigated smoking habits or body fatness (BMI) in relation to colorectal tumours. Those studies fairly consistently suggest that smoking and a high BMI markedly increase the risk of CRC in persons with LS. Other lifestyle factors, such as physical activity, alcohol or diet have not or only scarcely been studied. Lifestyle factors may indeed affect CRC risk in LS. However, more prospective studies with only confirmed MMR gene mutation carriers should be done to further elucidate the role of all lifestyle factors in CRC and in other types of cancer in persons with LS. Information on the role of lifestyle factors in the development of LS-associated cancers may help in establishing lifestyle and dietary recommendations with the ultimate goal of decreasing cancer risk in persons with LS.

Abstract 1398: Establishment and characterization of a clinically-relevant personalized hormone-dependent breast cancer tumor model.

Abstract Background: The START Patient Tumor Program was established to improve clinical outcomes for cancer patients by creating a biorepository of blood and cancer tissues for characterization and preclinical model development and testing. To date samples from over 1500 patients have been collected with over 400 models generated including 40 patient-derived breast tumor xenografts. These models can be used for personalized studies, particularly in situations where treatment options have been exhausted. In the current study a breast biopsy was collected from a 48 year old Hispanic female with recurrent, chemotherapy-refractory ER+/HER2+ metastatic breast cancer and implanted into an immune-deficient mouse. The resulting model was expanded and evaluated against eight FDA-approved and four investigational agents. Methods: ST340 ER+/HER2+ breast PDX model: The tumor sample from an inform-consented participant was implanted into nude mice and the established model confirmed by histologic analysis and linked with clinical treatment and outcome data. Activating mutation profiling was performed on fifty-two known cancer genes with extracted DNA using a PCR-based assay with customized primers. An efficacy study was performed testing various approved and investigational agents. Study endpoints included tumor volume and time from treatment initiation. Reported results included tumor growth inhibition or delay and regression. Results: Prior to treatment initiation, estradiol was withheld to confirm dependence and was found requisite for growth. Following treatment, results identified impressive sensitivity to the targeted therapy everolimus including tumor regressions and moderate sensitivity towards an aromatase inhibitor. Treatment with this combination regimen resulted in improved tumor markers and overall quality of life for an extended period of time. Following progression, subsequent treatment with a cytotoxic agent found active in the initial screen resulted in additional months of progression free disease. Conclusion: Participation in the START Patient Tumor Program provided beneficial data which improved clinical outcome for this patient demonstrating that personalized preclinical models of human cancer can predict useful agents for clinical treatment in select situations. Citation Format: Michael J. Wick, Teresa L. Vaught, Lizette Gamez, Jennifer Brown, Alyssa Moriarty, Anthony W. Tolcher, Drew W. Rasco, Amita Patnaik, Gladys Rodriguez, Ronald L. Drengler, Kyriakos P. Papadopoulos. Establishment and characterization of a clinically-relevant personalized hormone-dependent breast cancer tumor model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1398. doi:10.1158/1538-7445.AM2013-1398

Abstract 3627: Occupational asbestos exposure is associated with head and neck cancer.

Abstract Asbestos describes a group of naturally occurring silicate mineral fibers that were frequently used in industry during the 20th century due to their desirable flame retardant and tensile properties. Although use has fallen over the last three decades, exposure continues and the burden of disease is considerable. The primary routes of exposure to the fibers include inhalation and ingestion. Asbestos is a known risk factor for several malignant respiratory diseases, including lung cancer and mesothelioma, and has more recently been implicated in pharyngeal and laryngeal cancer. However, studies of asbestos and cancers of the larynx or pharynx with adequate sample-size and control for other risk factors for head and neck squamous cell carcinoma (HNSCC) such as smoking and drinking habit remain somewhat sparse. We report findings from a case-control study consisting of 934 incident HNSCC cases from the greater Boston region and 1180 population-based controls, frequency matched on age (+/- 3 years), sex, and town or neighborhood of residence. Study subjects completed a self-administered questionnaire that provided detailed data on history of asbestos exposure, sociodemographics and personal characteristics, alcohol and tobacco use, personal and family cancer history, and other relevant dietary, occupational, residential and medical exposures. Occupational asbestos exposure was dichotomized as exposed or never exposed based on self reported occupation data. Multivariate unconditional logistic regression was used to assess the association between asbestos exposure and HNSCC, overall and by primary tumor site and smoking history. A total of 217 cases (23.2%) and 226 controls (19.2%) reported an occupational exposure to asbestos. We observed a borderline association of asbestos exposure and laryngopharyngeal cancer (OR = 1.23, 95% CI: 0.95-1.59), adjusted for age, sex, race, smoking, alcohol consumption, and education. After stratifying by smoking history, a significant association was observed between asbestos exposure and laryngopharyngeal cancer among ever-smokers (OR = 1.36, 95% CI: 1.00-1.84). These observations are consistent with the mounting evidence that asbestos is a risk factor for pharyngeal and laryngeal cancer. Citation Format: Scott M. Langevin, Mattie H. O'Sullivan, Jennifer L. Valerio, Kate M. Applebaum, Melissa Eliot, Michael D. McClean, Karl T. Kelsey. Occupational asbestos exposure is associated with head and neck cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3627. doi:10.1158/1538-7445.AM2013-3627