Long-term Cancer Research Articles

Somatic evolution and global expansion of an ancient transmissible cancer lineage.

The canine transmissible venereal tumor (CTVT) is a cancer lineage that arose several millennia ago and survives by "metastasizing" between hosts through cell transfer. The somatic mutations in this cancer record its phylogeography and evolutionary history. We constructed a time-resolved phylogeny from 546 CTVT exomes and describe the lineage's worldwide expansion. Examining variation in mutational exposure, we identify a highly context-specific mutational process that operated early in the cancer's evolution but subsequently vanished, correlate ultraviolet-light mutagenesis with tumor latitude, and describe tumors with heritable hyperactivity of an endogenous mutational process. CTVT displays little evidence of ongoing positive selection, and negative selection is detectable only in essential genes. We illustrate how long-lived clonal organisms capture changing mutagenic environments, and reveal that neutral genetic drift is the dominant feature of long-term cancer evolution.

Abstract LB-179: Pre- and post-diagnosis body mass index, weight change, and prostate cancer-specific mortality among prostate cancer survivors in the US

Abstract Accumulating evidence suggests that excess body fatness is associated with an increased risk of aggressive prostate cancer. However, the roles of body mass index (BMI -kg/m2), reported before and after diagnosis, and weight change in long-term prostate cancer survival remain unclear. Prospective data from men diagnosed with non-metastatic prostate cancer between 1992 and 2013 were obtained from the American Cancer Society’s Cancer Prevention Study II Nutrition Cohort. Weight was self-reported on surveys completed at enrollment into the Nutrition Cohort in 1992, in 1997, and every 2 years thereafter. Pre-diagnosis BMI was from the first survey completed >1 year before diagnosis and post-diagnosis BMI from the first survey completed > 2 years after diagnosis to allow for treatment completion. BMI was classified as ideal (18.5-<25), overweight (25-<30), and obese (30+). Weight change was the difference in weight (lbs.) from pre- to post-diagnosis. Follow-up began on the date of diagnosis in pre-diagnosis analyses (n=9,867) and, to reduce the potential for reserve causation, 4-years after the post-diagnosis survey in post-diagnosis analyses (n=6,860). Follow-up ended at death or December 2014, whichever came first. Cox proportional hazard models were used to estimate cause-specific hazard ratios (HR) and 95% confidence intervals (95% CI), adjusted for age, race, education, initial treatment, stage, Gleason score, node involvement, comorbidities, pre-diagnosis BMI (weight change models only), smoking, alcohol, and physical activity. A total of 614 and 330 prostate cancer deaths occurred in the pre- and post-diagnosis cohorts, respectively. The median follow-up time was 10.6 years (interquartile range (IQR) =7.9) and 5.5 years (IQR=6.1) in the pre- and post-diagnosis cohorts, respectively. In pre-diagnosis multivariable models, BMI was not associated with prostate cancer-specific mortality (e.g., Obese vs Ideal: HR=1.09, 95% CI: 0.83, 1.42). In post-diagnosis models, compared to men with an ideal BMI, the hazard of prostate cancer-specific death was similar among overweight men (HR=1.08, 95%CI: 0.84, 1.39) and higher among obese men (HR=1.41, 95% CI: 1.02, 1.97). Compared to men who maintained their weight (± 5 lbs.), the hazard of prostate cancer-specific mortality was higher among men who gained > 10 lbs. (HR=1.33, 95%CI: 0.99, 1.77) or lost > 10 lbs. (HR=1.33, 95%CI: 0.92, 1.92), but was similar among men who gained or lost 5-10 lbs. Our results suggest that post-diagnosis obesity and weight gain may be associated with increased risk of prostate cancer-specific mortality. The suggestion of an inverse association between weight loss and higher prostate cancer-specific mortality in our study should be interpreted with caution as it is unknown whether weight loss occurring was intentional or due to advanced disease. Citation Format: Alyssa N. Troeschel, Eric J. Jacobs, W. Dana Flanders, Victoria L. Stevens, Terryl J. Hartman, Lauren E. McCullough, Ted Gansler, Ying Wang. Pre- and post-diagnosis body mass index, weight change, and prostate cancer-specific mortality among prostate cancer survivors in the US [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 LB-179.

Breast cancer survivors reduce accelerometer-measured sedentary time in an exercise intervention.

Cancer survivors are highly sedentary and have low physical activity. How physical activity interventions impact sedentary behavior remains unclear. This secondary analysis examined changes in sedentary behavior among breast cancer survivors participating in a physical activity intervention that significantly increased moderate-to-vigorous physical activity (MVPA). Insufficiently active breast cancer survivors were randomized to a 12-week physical activity intervention (exercise arm) or control arm. The intervention focused solely on increasing MVPA with no content targeting sedentary behavior. Total sedentary behavior, light physical activity (LPA), and MVPA were measured at baseline and 12weeks (ActiGraph GT3X+ accelerometer). Separate linear mixed-effects models tested intervention effects on sedentary behavior, intervention effects on LPA, the relationship between change in MVPA and change in sedentary behavior, and potential moderators of intervention effects on sedentary behavior. The exercise arm had significantly greater reductions in sedentary behavior than the control arm (mean - 24.9min/day (SD = 5.9) vs. - 4.8min/day (SD = 5.9), b = - 20.1 (SE = 8.4), p = 0.02). Larger increases in MVPA were associated with larger decreases in sedentary behavior (b = - 1.9 (SE = 0.21), p < 0.001). Women farther out from surgery had significantly greater reductions in sedentary behavior than women closer to surgery (b = - 0.91 (SE = 0.5), p = 0.07). There was no significant group difference in change in LPA from baseline to 12weeks (b = 5.64 (SE = 7.69), p = 0.48). Breast cancer survivors in a physical activity intervention reduced total sedentary time in addition to increasing MVPA. Both increasing physical activity and reducing sedentary behavior are needed to promote optimal health in cancer survivors. These results show that MVPA and sedentary behavior could be successfully targeted together, particularly among longer-term cancer survivors. This study is registered at www.ClinicalTrials.gov (NCT02332876).

Subsequent neoplasm risk associated with rare variants in DNA repair and clinical radiation sensitivity syndrome genes: A report from the Childhood Cancer Survivor Study.

10028 Background: Radiotherapy for childhood cancer is associated with strikingly elevated risk for developing subsequent neoplasms (SNs). Whether mutations in DNA repair and radiation sensitivity genes modulate SN risks is largely unknown. Methods: We conducted whole-exome sequencing in 5105 long-term childhood cancer survivors of European descent (mean follow-up = 32.7 years). SnpEff and ClinVar identified potentially damaging rare variants in 476 DNA repair or radiation sensitivity genes. Conditional logistic regression assessed SN risk associated with these variants aggregated by gene or pathway (N = 155 with ≥5 carriers). Controls were matched on sex, childhood cancer type and diagnosis age, radiation dose to the SN site, and survival. Exact p-values were calculated by permutation. Analyses used all survivors or subsets stratified on radiation dose. Results: A total of 1108 (21.7%) survivors developed at least one SN type known to be related to ionizing radiation exposure (e.g., breast cancer, basal cell carcinoma, meningioma, thyroid cancer, sarcoma). Radiation-related SN risk was associated with homologous recombination (HR) gene variants for SN sites that received &gt; 0- &lt; 10 Gy (20.9% cases, 11.0% controls; odds ratio [OR] = 2.20, 95% confidence interval [CI] 1.52-3.18; P = 1.41x10-4), most notably for FANCM (3.1% cases, 0.5% controls; OR = 9.91, 95%CI 3.73-26.4; P = 2.85x10-4). For radiation-related SNs at sites with higher doses (≥10 Gy), associations were not observed for the HR pathway (14.4% cases, 12.4% controls, P = 0.17) but were observed for two individual genes implicated in double-strand DNA break repair, EXO1 (1.8% cases, 0.4% controls; OR = 6.50, 95%CI 3.49-12.1; P = 7.43x10-4) and NEIL3 (0% cases, 1.0% controls; P = 3.23x10-4). Conclusions: In this discovery study, we identified dose-specific novel associations between SN risk after radiotherapy for childhood cancer and potentially damaging rare variants in genes involved in double-strand DNA break repair, particularly HR. If replicated, these results could impact long-term screening of childhood cancer survivors and risk-benefit assessments of treatment approaches.

The CAROLE (CArdiac Related Oncologic Late Effects) Study: A Phase II, single-arm feasibility trial.

11569 Background: Long-term breast cancer survivors are at risk of late effects from cardiotoxic (tox) radiation (RT) and chemotherapy (chemo). However, there is a paucity of data to recommend appropriate cardiac screening for those ~10 years (yrs) after diagnosis (dx). This phase II, single arm study assessed multimodality screening in a heterogeneous cohort of long-term survivors. Methods: Our prospective, single center pilot study enrolled 201 (of 200 planned) eligible patients (pts): age 18-65 at dx, with treatment (tx) for breast cancer (any stage/tx) in 2004-2011 (≥6 yrs prior), with no cardiac disease (dz) at dx. The primary endpoint was presence of any cardiac dz (preclinical or clinical) on electrocardiogram (EKG), echocardiogram (echo), or coronary artery calcium CT (CAC CT); secondary endpoint included clinical (clin) dz alone. Subgroups assessed were: no tox chemo or RT (no tox), tox RT (left-sided) alone, tox chemo (anthracycline) alone, and both tox chemo and tox RT (tox chemoRT). Results: After enrollment (6/2017-7/2018), 200 pts had sufficient data for analysis. Median age was 50 (29-65) at dx, 63 (37-77) at imaging, and interval (dx to imaging) was 11.5 (6.7-14.5) yrs. There were 44% no tox, 31.5% tox RT, 16% tox chemo, and 8.5% tox chemoRT pts. Among all pts, 77.6% displayed evidence of any cardiac dz, 51.5% had clin dz. Per modality, rates of any and clin dz were: 27.1%/10% EKG, 50.0%/25.3% echo, and 50.8%/45.8% CAC CT. Among subgroups, these rates were: 73.9%/53.4% no tox, 82.5%/58% tox RT, 75%/38.7% tox chemo, and 82.4%/35.3% tox chemoRT (NS on χ2 test, p = .58/p = .15). Multivariable logistic regression with tox RT, tox chemo, and age as covariates, showed no significant tox RT (NS) or tox chemo effect (NS), however, increasing age was significantly associated with higher incidence of cardiac dz (p &lt; 0.01; OR = 1.12 per yr, 95% CI: 1.07-1.18). Conclusions: Among pts with a median of &gt; 10 yrs post breast cancer tx, multimodality CAROLE screening was feasible and showed high rates of cardiac dz (any/clin = 77.6%/51.5%) among all subgroups, including those without tox tx. This study provides evidence for long-term cardiac screening in a diverse group of breast cancer survivors and provides a novel pathway for evaluation. Clinical trial information: NCT03235427.

Changes in prostate-specific antigen midway through salvage radiotherapy may be associated with long-term outcomes

To examine the relationship between changes in prostate-specific antigen (PSA) by midpoint of salvage radiotherapy (SRT) for biochemically recurrent prostate cancer and long-term clinical outcomes. We conducted a retrospective study of men treated with SRT for biochemically recurrent prostate cancer at a single practice from 2004 to 2016. Patients were grouped based on PSA response at treatment midpoint: group 0, no change; group 1, decrease; group 2, increase. The primary endpoint was clinical failure measured from time of SRT completion and defined as serum PSA ≥ 0.2 ng/mL above post-radiotherapy nadir, initiation of androgen deprivation therapy, development of bone metastasis, or death from prostate cancer. The Kaplan-Meier method was used to estimate freedom from clinical failure for each group, and differences between groups were examined using pairwise multiple comparison. Median follow-up was 51.6 months (range, 3.3–138.0). Of 76 eligible men, 13.1% experienced no change in PSA at midpoint of SRT (group 0), 68.4% experienced a decrease (group 1), and 18.4% experienced an increase (group 2). Four-year freedom from clinical failure rates were as follows: group 0, 60.0%; group 1, 58.3%; and group 2, 41.7%. Median time to clinical failure was 71.7 months (95% confidence interval, 46.9–96.5) for group 1; 26.8 months (95% confidence interval, 0.0–55.9) for group 2; and was not reached for group 0. There was a significant difference in four-year freedom from clinical failure between groups 1 and 2 (p = 0.036). PSA changes by the midpoint of SRT predict long-term prostate cancer control with increases in PSA associated with decreased freedom from disease progression.

Characterizing unconventional T cells in the tumor microenvironment of metastatic osteosarcoma

Abstract Osteosarcoma is the most common bone cancer and typically affects patients in the second decade of life. Current treatment methods have not proven effective for treating reoccurring or metastatic osteosarcoma (mOS) given the 5-year survival rate of 15–30%. Previous work has shown anti-PD-L1 combined with anti-CTLA-4 improves survival of mOS in mice from 0% in no treatment mice to 60% in treated mice. To further improve survival, we analyzed tumor infiltrating lymphocytes (TILs) in mice over time and discovered CD4hiCD8hiPD-1hi T cells consistently appeared in the tumor microenvironment (TME) after approximately two months. To determine whether these CD4hiCD8hi, or double positive (DP) cells, were candidates for immune therapy, TILs from mice with long-term cancer were stained for CD3 to confirm T cell lineage, CD44 to verify activation, and Qa-2, which is first expressed during the stage IV single positive phase of T cell maturation and is therefore a marker to distinguish mature from immature T cells. The DP TILs were found to be activated, mature T cells that are distinct from DP immature thymocytes. The DP TILs were further compared to splenocytes and were determined to be concentrated in the TME rather than resulting from a systemic change in the immune system. Finally, the presence of DP T cells in the lungs was found to be unique to long-term lung metastases when lung tissues from age-matched healthy mice were obtained and processed alongside experimental lung metastases. Overall, mature and activated DP T cells concentrate in the TME of long-term lung metastases of mOS.

Improving cancer symptom awareness and help-seeking among adults living in socioeconomically deprived communities in the UK using a facilitated health check: A protocol for the Awareness and Beliefs About Cancer (ABACus) Randomised Control Trial

BackgroundCancer survival is lower in socioeconomically deprived communities, partly due to low awareness of symptoms, negative beliefs and delayed help-seeking. We developed an interactive health check questionnaire facilitated by trained lay advisors. It entails 29 questions about background, lifestyle and health with tailored behaviour change advice. Personalised results are printed using a traffic light (red/amber/green) system, highlighting areas where action should be taken. This is an individually randomised control trial to test effectiveness of the health check on symptom recognition.MethodsA total 246 participants aged 40+ years will be recruited from community and healthcare settings in socioeconomically deprived areas of Yorkshire and South Wales. Participants will be randomised to receive the health check or standard care (1:1 ratio). Outcome measures include: adapted Awareness and Beliefs about Cancer (primary outcome), brief State Trait Anxiety Inventory, intentions and motivation to adopt recommended health behaviours (early symptom presentation, cancer screening and lifestyle behaviours), adapted Client Service Receipt Inventory, brief medical history/screening and demographic questionnaire at: baseline; 2-weeks; and 6-months post-randomisation. A purposive sample of intervention sessions will be audio-recorded (n = 24) and half will additionally be observed (n = 12). Semi-structured interviews will take place at 2-weeks (n = 30) and 6-months (n = 15–20) post-randomisation. The primary analysis will compare cancer symptom recognition scores between arms at 2-weeks. Secondary analysis will assess cancer beliefs, barriers/time to presentation, screening and lifestyle behaviours, anxiety and costs. A process evaluation will assess intervention fidelity, dose and contamination.The London-Surrey NHS Research Ethics Committee (Ref: 17/LO/1507) approved this trial.DiscussionThis is a trial of a theoretically underpinned complex intervention which has undergone phase 1 and 2 development work. The findings will evaluate evidence about the effect of the health check on symptom awareness. Although there are few exclusion criteria there are limitations regarding the population we are able to reach, who may have even higher risks of late diagnosis and poor cancer prognosis. However, the health check has the potential to improve cancer symptom awareness and encourage early help-seeking behaviour in deprived populations, thereby reducing inequalities in longer term cancer outcomes.Trial RegistrationRetrospectively registered with ISRCTN (Ref:ISRCTN16872545) on 12.01.2018.

HSR19-104: Patterns of Providers’ Mammogram Referrals for Asymptomatic Breast Cancer Survivors

Background: NCCN Guidelines recommend annual mammography for surveillance in asymptomatic women diagnosed with breast cancer. There is limited evidence to support which type of mammogram—screening or diagnostic—should be ordered for asymptomatic breast cancer survivors. Our objective was to assess the referral patterns for mammograms in 2 breast clinics: survivorship (SC) and oncology (OC). Methods: A retrospective analysis of institutional databases was conducted to identify a convenience sample of women with limited invasive breast cancer who were (1) alive 5 years post-treatment and (2) seen at a SC or OC visit scheduled from January 1 to December 31, 2015. The primary outcome was women who received a diagnostic or screening mammogram during the 2015 calendar year. Demographic, clinical, and mammogram characteristics were also analyzed. Simple descriptive statistics were used to aggregate and compare data. Chi-square analysis tested for statistical significance. Results: A convenience sample of 354 cases was identified. Of those, 247 met the eligibility criteria for this analysis, SC=147 and OC=100. In this cohort, the mean age of diagnosis was 50.42 (±11.12), the majority were white (74.1%), and most received a diagnostic mammogram (64.4%). A greater proportion of diagnostic mammograms were ordered for women seen in OC (40.1%) vs SC (24. 3%). This finding was statistically significant (P=.00). Overall, 91.9 % of the mammogram results were negative and with a low proportion of “positive” (2.0%) or “need for additional imaging testing” (6.1%) reported. Recurrence rates in this cohort were also found to be low (1.6%). Conclusions: In this cohort, we found a difference in the type of mammogram ordered by providers in dedicated survivorship or medical oncology clinics. Our findings suggest that despite the greater use of diagnostic mammograms among this cohort of long-term breast cancer survivors, the overall proportion of positive findings, further imaging tests, or recurrence rates was low. It is concerning that many asymptomatic breast cancer survivors continue to receive a diagnostic mammogram as part of their surveillance visit. Further studies are needed to identify the emotional, financial, and physical toxicities associated with diagnostic mammograms.

Abstract P284: The Chemotherapeutic Agent Docetaxel Disrupts Mitochondrial Energetics in 3D Human Bioengineered Myobundles

Taxanes (i.e. docetaxel, (TAX)) comprise the first line-treatment for breast cancer (BC), mostly in combination with anthracyclines like doxorubicin (DOX). The efficacy of these drugs as antineoplastic agents has helped to boost 10-year survival rates to &gt; 90%, leading to a fast-growing population of over 3 million BC survivors in the US. However, epidemiological evidence shows that the highly abrasive nature of these therapies can give rise to a vicious cycle of metabolic decline and physical inactivity that compromises quality of life and increases risk of numerous musculoskeletal and cardio-metabolic disorders including arthritis, sarcopenic obesity, cardiovascular disease and type 2 diabetes. Major side effects of TAX include peripheral neuropathy, arthralgia, myalgia and muscle weakness. Taxanes act primarily by stabilizing microtubules (MTs), which causes cell cycle arrest. Importantly, MT dynamics can also impact mitochondrial function. For example, the MT protein unit, tubulin, can bind to the outer mitochondrial protein channel, VDAC, and thereby affect ATP transport to the cytosol. Herein, we sought to test the hypothesis that TAX exacerbates DOX-induced mitochondrial dysfunction, which is thought to underlie anthracyclines’ cardiotoxicity. To this end, we leveraged a newly developed 3-D bioengineered model of human muscle organoids (myobundles), derived from primary human skeletal muscle progenitor cells (HSkM), to study mechanisms of TAX-induced myotoxicity and its interactions with DOX. Preliminary findings in primary HSkM cells exposed to 3 daily x 3 h treatments with TAX (1 - 100 nM) +/- 10 nM DOX caused a robust ~10-fold acetylation of a-tubulin at lysine 40 (AcK40), reflecting marked stabilization of MTs. TAX treatment decreased basal and ATP-linked respiration (JO 2 ) up to 30 % (p&lt;0.05), in a dose-dependent manner. However, maximal uncoupled JO 2 (+FCCP) remained unchanged, suggesting TAX disrupts mitochondrial thermodynamics and energy transfer, rather than maximal oxidative phosphorylation capacity. Exposure of 3D myobundles to a TAX+/-DOX regimen that mimicked human pharmacokinetics post-infusion led to a 30-fold increase (p&lt;0.005) in AcK40 a-tubulin. TAX alone induced a biphasic JO 2 response to ADP (KM ADP 2- and 4-fold higher, p&lt;0.05), but when combined with DOX there was a 50 % loss in maximal JO 2 (p&lt;0.005) with no changes in KM ADP . We hypothesize that the TAX-driven stabilization of MTs leads to detrimental MT-mitochondria interactions that disrupt ATP/ADP transfer between cellular compartments, exacerbating DOX toxicity and ultimately impairing muscle function. The present findings provide novel insights into the mechanisms of TAX-induced myotoxicities, which is of paramount importance for developing therapeutic strategies to improve cardiovascular health and quality of life of long-term breast cancer survivors.

Racial differences in long-term prostate cancer specific mortality following conservative management for low-risk prostate cancer: A population-based study.

121 Background: It is uncertain whether the same criteria for active surveillance can be applied universally across races. This population-based study was undertaken to quantify racial differences in long-term risk of prostate cancer-specific mortality (PCSM) among patients with low-risk prostate cancer (PCa) receiving conservative management. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients who had low-risk PCa (T1-T2a &amp; Gleason 6 &amp; PSA ≤ 10 ng/mL &amp; N0 &amp; M0) diagnosed in 2004 – 2015 and did not receive radical prostatectomy or radiation therapy within one year of diagnosis. Kaplan-Meier analysis was used to calculate PCSM. The Clopper-Pearson method was used to calculate associated 95% confidence intervals. Hazard ratio of PCSM among those with a high PSA (PSA 4-10) compared to those with a low PSA (PSA &lt; 4) was calculated using Cox proportional hazards models adjusted for covariates (including age, race, marital status, insurance status, U.S. region, year of diagnosis, and AJCC clinical tumor stage). Results: Among 33,740 patients with low-risk PCa, long-term PCSM varied with race and PSA levels at diagnosis. For instance, 10-year PCSM was 2.62% (95% CI: 1.15%-5.05%) among African Americans with PSA 4-10 and 0.98% (95% CI:0.16%-3.12%) among Caucasian patients with PSA &lt; 4. There was no significant statistical interaction between race and PSA level on PCSM (p = 0.81). After adjusting for potential confounders, men with PSA 4-10 experienced 2-fold higher PCSM relative to those with PSA &lt; 4 (HR = 1.96, p = 0.011) and African Americans men experienced a 43% higher PCSM compared to Caucasians (HR = 1.43, p = 0.03). Conclusions: Among men diagnosed with low-risk PCa, long-term PCSM varies by race and PSA at diagnosis. More refined risk stratification may improve PCa management among low-risk PCa patients. [Table: see text]

Towards a more precise and individualized assessment of breast cancer risk.

Many clinically based models are available for breast cancer risk assessment; however, these models are not particularly useful at the individual level, despite being designed with that intent. There is, therefore, a significant need for improved, precise individualized risk assessment. In this Research Perspective, we highlight commonly used clinical risk assessment models and recent scientific advances to individualize risk assessment using precision biomarkers. Genome-wide association studies have identified >100 single nucleotide polymorphisms (SNPs) associated with breast cancer risk, and polygenic risk scores (PRS) have been developed by several groups using this information. The ability of a PRS to improve risk assessment is promising; however, validation in both genetically and ethnically diverse populations is needed. Additionally, novel classes of biomarkers, such as microRNAs, may capture clinically relevant information based on epigenetic regulation of gene expression. Our group has recently identified a circulating-microRNA signature predictive of long-term breast cancer in a prospective cohort of high-risk women. While progress has been made, the importance of accurate risk assessment cannot be understated. Precision risk assessment will identify those women at greatest risk of developing breast cancer, thus avoiding overtreatment of women at average risk and identifying the most appropriate candidates for chemoprevention or surgical prevention.

Abstract P4-10-17: Plasma metabolomic signatures associated with long-term breast cancer risk in the SU.VI.MAX prospective cohort

Abstract Purpose: Breast cancer is a major cause of death in occidental women. Mechanisms involved in its etiology remain misunderstood. Metabolomics is a powerful tool which may help elucidating novel biological pathways and identify new biomarkers in order to predict breast cancer well before symptoms appear. The aim of this study was to investigate whether untargeted metabolomic signatures from blood draws of healthy women could contribute to better understand and predict the long-term risk of developing breast cancer. Methods: A nested case-control study was conducted within the SU.VI.MAX prospective cohort (13 years of follow-up) to analyze baseline plasma samples of 211 incident breast cancer cases and 211 matched controls by LC-MS mass spectrometry. Multivariable conditional logistic regression models were computed. Results: 83 ions were significantly associated (corrected-pvalue &amp;lt;0.05) with breast cancer risk. Notably, we observed that a lower plasma level of O-succinyl-homoserine and higher plasma levels of valine/norvaline, glutamine/isoglutamine, 5-aminovaleric acid, phenylalanine, tryptophane, γ-glutamyl-threonine, ATBC, 2-amino-cyanobutanoic acid and pregnene-triol sulfate were associated with an increased risk of developing breast cancer during follow-up. Corrected-pvalues ranged from 0.009 (OR=1.43[1.14-1.78] for phenylalanine and OR=1.45[1.15-1.83] for valine/norvaline) to 0.03 (OR=1.28[1.03-1.58] for 2-amino-cyano-butanoic acid). Conclusion: Several pre-diagnostic plasmatic metabolites are strongly associated with long-term breast cancer risk. If confirmed in other independent cohort studies, these results could help to identify healthy women at higher risk of developing breast cancer in the subsequent decade and to propose a better understanding of the complex mechanisms involved in its etiology. Trial registration: SU.VI.MAX, clinicaltrials.gov NCT00272428. Registered 3 January 2006 Keywords: Metabolomics, breast cancer, mass spectrometry, plasma, prospective study Citation Format: Lucie L, Céline D, Bernard L, Aicha D, Adrien R, Marie-Paule V, Mélanie P, Marie L, Tom F, Delphine C, Laurent Z, Pilar G, Serge H, Mélanie D, Valentin P, Bernard S, Paule L-M, Emmanuelle K-G, Nathalie D-P, Claudine M, Stéphanie D, Estelle P-G, Mathilde T. Plasma metabolomic signatures associated with long-term breast cancer risk in the SU.VI.MAX prospective cohort [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-10-17.

Abstract P1-08-12: Trends in incidence of bilateral breast cancer: A Population-based comparative study of the United States and Japan

Abstract Background: Previous studies demonstrated that the incidence rate of invasive contralateral breast cancer (CBC) was 5% within the first 10 years after the primary breast cancer (BC). However improving long-term breast cancer survivorship and advancements in diagnostic imaging have resulted in an increased detection of bilateral breast cancer (BBC), and trends of bilateral invasive and in situ breast cancer are not well established. The aim of this study was to assess national trends of BBC incidence of the United States (US) and Japan. Methods: The Surveillance, Epidemiology, and End Results (SEER) database (1973-2014) and the clinical database of Breast Oncology Center of Cancer Institute Hospital in Tokyo, Japan (Ganken) database (1946-2015) were used to identify nSEER=11,771 and nGanken=1,499 women diagnosed with BBC, respectively. BBC was defined as invasive BC and/or ductal or lobular carcinoma in situ diagnosed in both breasts simultaneously or after primary breast cancer diagnosis. BBC was grouped into synchronous or metachronous BBC by the interval between first BC and contralateral BC; synchronous cases were defined as CBC diagnosed at the same time or within an interval of 1 year from primary BC diagnosis whereas metachronous cases were defined as a diagnosis occuring 1 year following the primary BC. We assessed trends of BBC incidence and characteristics of BBC cases between the two countries. To determine temporal trends in the incidence of BBC and proportion of the characteristics, we compared them using the Cochrane-Armitage test for trend. Results: The rates of BBC have significantly increased in both countries (Table 1, 2) [1975: 2.6%; 2014: 7.5% in SEER (p&amp;lt;0.001), 1946-1980: 3.3%; 2011-2015: 10.7% in Ganken (p&amp;lt;0.001)]. The increase was identified in both synchronous and metachronous BBC. In SEER, 40% of synchronous BBC were found as in situ BC and about 15% of BBC presented as invasive lobular carcinoma. More recently, CBC was more likely to be diagnosed at early stages (in situ and local disease) than in previous years [1975: 65%; 2014: 85% in SEER (p&amp;lt;0.001)]. The interval between first BC and contralateral BC have shortened, and CBC were more likely to be operated simultaneously in both countries [1985: 40%; 2014: 51% in SEER, 1946-1980: 24%; 2011-2015: 74% in Ganken]. [Table 1]Crude rates of BBC in all breast cancer in SEER 19751985199520052014All breast cancer941813618258766016471505BBC and rates (%)249 (2.6%)790(5.8%)1421(5.5%)3336(5.6%)5381(7.5%)Rates of synchronous BC2.1%2.8%2.3%2.6%3.5%Rates of metachronous BC0.5%3.0%3.2%3.0%4.0%BBC: Bilateral breast cancer [Table 2]Crude rates of BBC in all breast cancer in Ganken 1946-19801981-19851991-19952001-20052011-2015All breast cancer47772162280637915241BBC and rates (%)157(3.3%)110(5.1%)188(6.7%)298(7.9%)559(10.7%)Rates of synchronous BC1.0%1.9%2.0%2.7%4.9%Rates of metachronous BC2.3%3.2%4.7%5.2%5.8% Conclusion: In the modern era, the number of BBC cases have increased and are more likely to be found at an early stage. Further studies are needed to demonstrate the usefulness of early detection of CBC and to define the best means to tailor therapy for patients with bilateral disease. Citation Format: Sakai T, Ozkurt E, Desantis S, Wong S, Rosenbaum L, Zheng H, Ohno S, Golshan M. Trends in incidence of bilateral breast cancer: A Population-based comparative study of the United States and Japan [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-12.

Abstract IA34: Mapping immune recognition of non-self neoantigens in human pancreatic cancer

Abstract Endogenous T-cell responses to cancer-specific mutations (neoantigens) are a common denominator of successful immunotherapies. However, endogenous neoantigen-specific T cell immunity in immunotherapy refractory tumors remains poorly characterized. Pancreatic ductal adenocarcinoma (PDAC) is the prototypical immunotherapy refractory cancer: response rates to single-agent checkpoint blockade are &amp;lt;2%, and 5-year survival with conventional therapies remains &amp;lt;7%. In these rare 7% of PDAC patients that survive &amp;gt; 5 years, T cell immunity has been linked to their exceptional outcome however the relevant antigens remained unknown. We sought to identify the landscape, antigenic potential, and T cell functional states induced by neoantigens in rare long-term pancreatic cancer survivors. Using genetic, immunologic, and computational techniques, we recently reported that tumors with the highest predicted neoantigen number and the greatest density of CD3+CD8+ infiltrates together, but neither parameter alone, could identify long-term survivors, suggesting differential inherent neoantigen immunogenicity. To investigate the specific neoantigen qualities promoting differential immunogenicity, we developed a fitness model that quantifies neoantigen immunogenicity based on estimations of the relative MHC binding affinity of each neoantigen to its wild type counterpart, as well as a nonlinear dependence on sequence similarity of neoantigens to known antigens. Our neoantigen quality fitness model identified long-term survivors in two independent PDAC datasets, as well as predicted survival in anti-CTLA4 treated melanoma patients, and anti-PD-1 treated lung cancer patients. In long-term PDAC survivors, we detected high quality neoantigen-specific intratumoral T cell clones persisting in the blood up to 12 years after primary tumor removal, with both unique clonal and phenotypic profiles. Our results identify neoantigens with unique qualities as T cell targets in both endogenous and immunotherapy treated cancers. Neoantigen quality can therefore inform rational neoantigen immunogenicity predictions that may guide patient and target selection for immunotherapies. Citation Format: Marta Luksza, Joanne P. Leung, Alexander Solovyov, David Redmond, Miriam Merad, Sacha Gnjatic, Christine Iacubuzio-Donohue, Ronald P. DeMatteo, Timothy A. Chan, Jedd Wolchock, Steven D. Leach, Benjamin D. Greenbaum, Taha Merghoub, Vinod P. Balachandran. Mapping immune recognition of non-self neoantigens in human pancreatic cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA34.

Long-term gastric cancer risk in male smokers with atrophic corpus gastritis

Objectives: The aim of this study was to evaluate long-term gastric cancer risk in male smokers with and without atrophic gastritis.Materials and methods: A total of 22,346 elderly male smokers participated in the Helsinki Gastritis Study between the years 1989 and 1993. Serum pepsinogen I (PGI) was measured for the men, and 2,132 men with low PGI (<25 µg/L; a marker of atrophic corpus gastritis) were invited to undergo gastroscopy because of increased gastric cancer risk. Endoscopy was performed to 1,327 men, who were followed up for a median of 13.6 years and a maximum of 25.3 years thereafter. In addition, the gastric cancer risk of men with low PGI was compared to that of the men with normal PGI and to the general Finnish male population of the same age.Results: Thirty-five cases of gastric cancer were diagnosed in men with gastroscopy during the follow-up. The incidence rate was 1.94 per 1000 patient years. The men with a history of gastric surgery (n = 180) due to a benign cause had even higher gastric cancer incidence (3.2 per 1000 patient-years). Gastric cancer risk was highest in men with marked intestinal metaplasia in primary biopsies. Compared to the general Finnish male population of the same age, the cancer risk was 1.13 times higher in male smokers with normal serum PGI, and 2.43 times higher in men with low serum PGI.Conclusion: In male smokers, atrophic gastritis and intestinal metaplasia increase the risk of gastric cancer.

On the use of flexible excess hazard regression models for describing long-term breast cancer survival: a case-study using population-based cancer registry data

BackgroundBreast cancer prognosis has dramatically improved over 40 years. There is, however, no proof of population ‘cure’. This research aimed to examine the pattern of long-term excess mortality due to breast cancer and evaluate its determinants in the context of cancer registry data.MethodsWe used data from the Geneva Cancer Registry to identify women younger than 75 years diagnosed with invasive, localised and operated breast cancer between 1995 and 2002. Flexible modelling of excess mortality hazard, including time-dependent (TD) regression parameters, was used to estimate mortality related to breast cancer. We derived a single “final” model using a backward selection procedure and evaluated its stability through sensitivity analyses using a bootstrap technique.ResultsWe analysed data from 1574 breast cancer women including 351 deaths (22.3%). The model building strategy retained age at diagnosis (TD), tumour size and grade (TD), chemotherapy and hormonal treatment (TD) as prognostic factors, while the sensitivity analysis on bootstrap samples identified nodes involvement and hormone receptors (TD) as additional long-term prognostic factors but did not identify chemotherapy and hormonal treatment as important prognostic factors.ConclusionsTwo main issues were observed when describing the determinants of long-term survival. First, the modelling strategy presented a lack of robustness, probably due to the limited number of events observed in our study. The second was the misspecification of the model, probably due to confounding by indication. Our results highlight the need for more detailed data and the use of causal inference methods.

Incidence of Medication-Treated Depression and Anxiety Associated with Long-Term Cancer, Cardiovascular Disease, Diabetes and Osteoarthritis in Community-Dwelling Women and Men

Background: Physical chronic conditions may increase the risk of mental disorders but the findings are inconsistent between studies and whether the associations differed between genders is unclear. This study aimed to examine whether long-term cancer, cardiovascular disease, diabetes and osteoarthritis were associated with higher risks of incident depression and anxiety and these associations in women compared with men. Methods: We included 115,094 participants (54.3% women) aged 45-64 years from the 45 and Up Study who were free of depression, anxiety, and Parkinson's disease at baseline (2006-2009). The incidence of depression and anxiety was identified using claim databases during follow-up until December 2016. Cox regression models were used to examine the association of cancer, cardiovascular disease, diabetes, and osteoarthritis at baseline with incident depression and anxiety. Findings: During a mean eight-year follow-up (958,785 person-year), the cumulative incidence of depression and anxiety was 12·5% and 5·9% in the healthy population. The hazard ratios ([HRs] (95% CI) VS healthy population) for incident depression associated with long-term cancer, cardiovascular disease, diabetes, and osteoarthritis were 1·19 (95% CI: 1·13-1·25), 1·08 (1·00-1·16)), 1·18 (1·09-1·28), and 1·94 (1·80-2·10), respectively. The corresponding HRs (95% CIs) for incident anxiety were 1·11 (1·03-1·20), 1·26 (1·14-1·39), 1·10 (0·98-1·24), and 2·01 (1·80-2·23), respectively. The positive association between cancer and incident depression was more evident in men (HR (95% CI): 1·24 (1·13-1·35) than in women (1·14 (1·07- 1·21). Long-term diabetes was an independent risk factor for incident anxiety in men (1·21 (1·02-1·44) but not in women (1·09 (0·93-1·28)). Other associations were significant in men and women. Interpretation: Long-term osteoarthritis, cardiovascular disease, and cancer were independent risk factors for incident depression and anxiety in both genders with osteoarthritis having the highest relative risk. Depression screen deserves more concern in men with long-term cancer and anxiety screen in men with long-term diabetes. Funding Statement: Professor Mingguang He receives support from the University of Melbourne at Research Accelerator Program and the CERA Foundation. The Centre for Eye Research Australia (CERA) receives Operational Infrastructure Support from the Victorian State Government. The specific project is funded by Australia China Research Accelerator Program at CERA. Professor Mingguang He is also supported by the Fundamental Research Funds of the State Key Laboratory in Ophthalmology, National Natural Science Foundation of China (81420108008). The sponsor or funding organization had no role in the design or conduct of this research. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The study protocol was approved by the Royal Victorian Eye and Ear Hospital Human Research Ethics Committee. Participants provided consent to follow-up and link their data to routine health datasets.

B-type natriuretic peptide plasma level in 5-year breast cancer survivors after radiotherapy

Background: Left-sided breast cancer patients treated with radiotherapy (RT) are at risk for late radiation-induced cardiovascular complications.Aim: The aim of this study was to investigate the BNP plasma levels in long-term breast cancer survivors who received only RT as well to assess whether cardiac dose was associated with BNP values.Methods: Plasma samples for BNP measurement were repeated in 29 patients (63 ± 11 years) who were alive at 5 years after radiotherapy, free of heart disease and available to provide new blood sample. All patients had BNP measurements at baseline. The ΔBNP was measured to analyze the role of marker variations. No patients received chemotherapy.Results: The mean cardiac and ventricle dose were 2.1 ± 1.0 (range 0.02–4.5) Gy and 3.0 ± 1.7 (range 0.02–7.6), respectively. Median value of BNP was 47 pg/mL (interquartile ranges, 26–58.2 pg/mL) at baseline, and 34 pg/mL (interquartile ranges, 17.5–54 pg/mL) at 5 years after radiotherapy. There was no significantly different between two measurements (p = ns). Fifteen (52%) reported an improvement in BNP levels, 1 (3%) no changes and 13 (45%) reported a worsening. There was no correlation between ΔBNP and age (p = ns).When patients were stratified according to the median value of dose–volume data, ΔBNP was significantly higher in patients with increased cardiac Dmean (p = .02) and left ventricle Dmean (p = .009).Conclusion: At 5 years after radiotherapy, median plasma BNP levels remained within the normal range, but the delta-BNP levels are directly related to the heart and ventricular dose received.

Addressing health disparities in survivors of breast cancer through lifestyle modifications and group support.

177 Background: Obesity and inactivity have been shown to adversely affect outcomes in survivors of breast cancer. These factors may contribute to poorer outcomes in women of black and Hispanic populations, and those from lower socioeconomic backgrounds. We sought to improve overall well-being and limit weight gain in patients from these underserved populations through a group lifestyle intervention in a public hospital setting. Methods: 46 women were recruited and gave informed consent after completion of adjuvant chemotherapy for stage I-III breast cancer to participate in this feasibility pilot program. Blood work, body measurements, diet, two-minute walk tests, and PHQ9 depression scores were collected at the first and last of six monthly sessions. The group classes were led by a registered dietician and included diet and light exercise instruction at each visit. Results: Patient demographics and results are in the table below. Trends for non-completers included younger age, ethnicity, no hormonal therapy, lower baseline weight, lower HOMA IR, and dropout after two sessions. Among the 40% who completed all six sessions, there was a trend toward greater well-being (lower PHQ) with slight weight gain and increased insulin resistance. Completers tended to start in the same cohort and were more likely to complete if they attended more than two visits. Conclusions: Greater well-being may be an important outcome for group lifestyle improvement programs in populations with disparities. Motivations for better attendance may include group bonding. Participants will continue to be followed to obtain information on long-term weight change and cancer recurrence.[Table: see text]