Long-term Breast Cancer Survivors Research Articles

Abstract NG12: From cholesterol regulation to tumor suppression: Pcsk9 as a novel target for cancer immunotherapy

Abstract NG12: From cholesterol regulation to tumor suppression: Pcsk9 as a novel target for cancer immunotherapy

Individual courses and determinants of fear of cancer recurrence in long-term breast cancer survivors with and without recurrence

ObjectiveThis study investigated the prevalence, individual courses, and determinants of fear of cancer recurrence (FoR) in long-term breast cancer survivors (BCSs) with and without recurrence.MethodsA total of 184 breast cancer survivors were surveyed at four measurement time points: during hospitalization (T1), 10 weeks (T2), 40 weeks (T3), and 5–6 years (T4) after hospital discharge. Descriptive statistics, chi-square tests, and logistic regression were performed.ResultsRespondents were females and 57 years old, on average. At T1, T3, and T4, 54.8%, 31.6%, and 29.7% of BCSs, respectively, were classified as having dysfunctional levels of FoR. Dysfunctional FoR decreased from T1 to T3 (χ2(1) = 17.11, p = 0.000; N = 163) and remained stable afterwards. Eight subgroups of individual courses of FoR over time could be described: (1) constant functional FoR; (2) constant dysfunctional FoR; (3) improving from dysfunctional to functional FoR from T1 to T3; (4) improving from dysfunctional to functional FoR from T3 to T4; (5) worsening from functional to dysfunctional FoR from T1 to T3; (6) worsening from functional to dysfunctional FoR from T3 to T4; (7) dysfunctional FoR at T1 and T4, and functional FoR in between; and (8) functional FoR at T1 and T4, and dysfunctional FoR in between. Logistic regression analysis revealed that being divorced/widowed, showing high levels of fatigue, being treated by chemotherapy, and having low confidence in treatment were associated with dysfunctional FoR 5 to 6 years after diagnosis (Nagelkerkes’ Pseudo-R2 = 0.648).ConclusionsThe findings reveal that FoR is a significant issue in long-term BCSs and has the potential to become a persistent psychological strain. We emphasize the need for increased awareness of FoR among BCSs and the need for support programs.

Health-Related Quality of Life in Very Long-Term Cancer Survivors 14-24 Years Post-Diagnosis Compared to Population Controls: A Population-Based Study.

Simple SummaryLittle is known about the health-related quality of life in very long-term cancer survivors 10 and more years post-diagnosis. Therefore, we compared the health-related quality of life of survivors of breast, colorectal, and prostate cancer (14–24 years post-diagnosis) with that of same-aged non-cancer controls, according to age, sex, and disease status (disease-free vs. stage IV, recurrence, metastasis, or second cancer). We found that the overall global health status/quality of life of cancer survivors more than a decade after diagnosis was slightly higher than that of population controls of the same age, but more symptoms and lower functioning were reported. Differences were small but statistically significant. Results differed by age, sex, and disease status. The findings point out the need for a comprehensive survivorship care program in order to monitor and treat potential late and long-term effects after the diagnosis and treatment of cancer. Survivorship care should be risk-adapted to survivors’ needs according to sociodemographic and clinical factors.(1) Background: Little is known about the health-related quality of life (HRQoL) in very long-term cancer survivors (VLTCS) 10 and more years post-diagnosis. The objective was to compare cancer survivors’ HRQoL 14–24 years post-diagnosis with that of same-aged non-cancer controls, stratified by age, sex, and disease status (disease-free vs. stage IV, recurrence, metastasis, or second cancer). (2) Methods: We recruited 2704 very long-term survivors of breast, colorectal and prostate cancer, and 1765 controls in German multi-regional population-based studies. The HRQoL was assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Differences in the HRQoL were estimated with multiple regression, controlling for age, sex (where appropriate), and education. (3) Results: The overall global health status/quality of life of VLTCS more than a decade after diagnosis was slightly higher than that of population controls of the same age, but more symptoms and lower functioning were reported. Differences were small but statistically significant. Results differed by age, sex, and disease status. (4) Conclusions: The findings point out the need for a comprehensive survivorship care program in order to monitor and treat potential late and long-term effects after the diagnosis and treatment of cancer. Survivorship care should be risk-adapted to survivors’ needs according to sociodemographic and clinical factors.

Involuntariness of job changes is related to less satisfaction with occupational development in long-term breast cancer survivors

PurposeConsidering that breast cancer survivors (BCSs) have been dealing with unwanted job changes after diagnosis, this study aimed to investigate involuntary job changes (unwanted modifications in employment since diagnosis) and explore the association between job changes, involuntariness, and occupational development satisfaction in BCSs 5–6 years after diagnosis.MethodsData were drawn from the mixed-methods breast cancer patients’ return to work (B-CARE) study. We surveyed 184 female BCSs who were working at the time of study enrollment during hospitalization (T1), 10 weeks after discharge (T2), 40 weeks after discharge (T3), and 5–6 years after diagnosis (T4) and used descriptive measures and stepwise linear regression models for data analysis.ResultsThe mean age of BCSs was 57 years. A total of 105 participants reported 410 job changes, of which 16.1% were reportedly (rather) involuntary. The most commonly reported involuntary changes were increased workload (15.2%) and increased scope of work (15.2%). In the final model, significant predictors of satisfaction with occupational development 5–6 years after diagnosis were age, state of health ΔT2–T3, state of health ΔT3–T4, and involuntariness of job changes.ConclusionsAlthough the number of job changes alone is not substantially associated with BCSs’ satisfaction with occupational development, experiencing involuntary job changes is. Sociodemographic, disease-related, and work(place)-related factors may influence occupational satisfaction among BCSs.Implications for Cancer SurvivorsThe findings indicate the importance of strengthening one’s ability to work as desired to prevent involuntary job changes and enable desired work participation in long-term support. The significance of workplace characteristics highlights the need for employers to encourage satisfying work participation.Trial registration numberGerman Clinical Trials Register (DRKS00016982), 12 April 2019

Use of health services among long-term breast cancer survivors in Spain: longitudinal study based on real-world data.

This study aimed to evaluate health service utilization in Spain among long-term breast cancer survivors and to compare it with that among women with no history of breast cancer. Study based on the SURBCAN cohort includes a sample of long-term breast cancer survivors and a sample of women without breast cancer from 5 Spanish regions. Healthcare utilization was assessed through primary care, hospital visits, and tests during the follow-up period (2012 to 2016) by using electronic health records. Annual contact rates to healthcare services were calculated, and crude and multivariate count models were fitted to estimate the adjusted relative risk of healthcare services use. Data were obtained from 19,328 women, including 6512 long-term breast cancer survivors. Healthcare use was higher among breast cancer survivors (20.9 vs 16.6; p < 0.0001) and decreased from >10 years of survival. Breast cancer survivors who underwent a mastectomy were more likely to have a primary care visit (RR = 3.10 95% CI 3.08-3.11). Five to ten years survivors were more likely to have hospital inpatient visits and imaging test compared to women without breast cancer (RRa = 1.35 95% CI 1.30-1.39 and RRa = 1.27 95% CI 1.25-1.29 respectively). This study shows higher use of health services in long-term breast cancer survivors than in women without breast cancer regardless of survival time. These results help to estimate the health resources needed for the growing group of breast cancer survivors and to identify risk factors that drive higher use of health services.

Fatigue among Long-Term Breast Cancer Survivors: A Controlled Cross-Sectional Study

Simple SummaryThe number of long-term breast cancer survivors is increasing. Earlier research showed that many breast cancer survivors suffer from fatigue during and shortly after treatment. Fatigue is distressing and can severely impact quality of life. In this research, we assessed whether the prevalence of fatigue is also elevated long after breast cancer treatment. We showed that even ten years after diagnosis, one in four breast cancer survivors experience fatigue. This is more than women of the same age without a history of cancer. In addition, we found that fatigue among long-term breast cancer survivors was associated with symptoms of depression and anxiety.Background: Fatigue is the most common and persistent symptom among women in the first five years after a breast cancer diagnosis. However, long-term prevalence of fatigue, among breast cancer survivors, needs further investigation. Aim: To compare fatigue experienced by long-term breast cancer survivors with that in a reference population and to evaluate the determinants of that fatigue. Design and Setting: A cross-sectional cohort study of 350 breast cancer survivors ≥5 years after diagnosis and a reference population of 350 women matched by age and general practitioner. Method: Fatigue was measured using the Multidimensional Fatigue Inventory (MFI-20), and a sum score of >60 (multidimensional fatigue) was the primary outcome. Logistic regression was applied to compare the prevalence of multidimensional fatigue between the survivor and reference populations, adjusted for body mass index (BMI) and for cardiovascular and psychological variables. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were estimated. Logistic regression was applied to evaluate the determinants of multidimensional fatigue among the survivors. Results: Breast cancer survivors (median 10 years after diagnosis), more often experienced multidimensional fatigue than the reference population (26.6% versus 15.4%; OR, 2.0 [95%CI, 1.4–2.9]), even after adjusting for confounders. The odds of multidimensional fatigue were also higher among survivors with symptoms of depression (32.2% versus 2.7%; OR, 17.0 [95%CI, 7.1–40.5]) or anxiety (41.9% versus 10.1%; OR, 6.4 [95%CI, 3.6–11.4]). Conclusion: One in four breast cancer survivors experience multidimensional fatigue and fatigue occurs more frequently than in women of the same age and general practitioner. This fatigue appears to be associated with symptoms of depression and anxiety.

P153 - Multimorbidity patterns among long-term breast cancer survivors: a Spanish population-based study

P153 - Multimorbidity patterns among long-term breast cancer survivors: a Spanish population-based study

Tired of feeling tired – The role of circulating inflammatory biomarkers and long-term cancer related fatigue in breast cancer survivors

BackgroundLow-grade inflammation has been associated with cancer related fatigue (CRF). However, most studies focused on CRF during or shortly after treatment. Longitudinal studies are rare with inconsistent results. We assessed the association of inflammatory biomarkers with total CRF and all subdomains (physical, cognitive, affective) in long-term breast cancer survivors. MethodPatients recruited between 2002 and 2005 provided information on CRF at first follow-up (FU1) (N = 1292) and second follow-up (FU2) (N = 1205), after a median of 6.2 years and 11.7 years, respectively. Associations of 11 inflammatory biomarkers with CRF at FU1 and at FU2 were assessed using linear regression models. Logistic regression models were used to compare patients fatigued at both time-points and those never fatigued (N = 932). ResultsC-reactive protein (CRP) was significantly associated with total CRF at FU1 (β = 1.47, 95%CI = 0.62–2.31, p = 0.0007), at FU2 (β = 1.98, 95 %CI = 0.96–2.99, p = 0.0001) and with persistent CRF (OR = 1.29, 95%CI = 1.13–1.47, p < 0.0001). IL-6 levels were associated with total CRF at FU1 (β = 1.01, 95%CI = 0.43–1.59, p = 0.0006), but not with CRF at FU2 or persistent CRF. No association remained significant after adjustment for relevant covariates. DiscussionCRP and Il-6 were associated with risk of CRF in long-term breast cancer survivors, but were not independent of other known risk factors, suggesting that currently studied inflammatory markers are not suitable to identify patients at risk of long-term CRF.

Association between physical activity and subsequent cardiovascular disease among 5-year breast cancer survivors.

To examine the association of physical activity among long-term breast cancer survivors on the occurrence of subsequent cardiovascular disease (CVD). We investigated the risk of CVD among 39,775 breast cancer patients who were newly diagnosed in 2006 and survived until 2011 within the Korean National Health Insurance Service database. Patients were followed up from 5years after breast cancer diagnosis to the date of CVD event, death, or December 31, 2018, whichever came earliest. Every 500 MET-mins/week correspond to 152, 125, and 62.5min per week of light-, moderate-, and vigorous-intensity physical activity, respectively. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for CVD were calculated using Cox proportional hazards regression by physical activity levels. Compared with those with physical activity of 0 MET-min/week, those with 1-499 (aHR 0.82, 95% CI 0.69-0.98), 500-999 (aHR 0.75, 95% CI 0.63-0.90), and ≥ 1,000 (aHR 0.76, 95% CI 0.63-0.93) MET-min/week of PA had lower risk of CVD. Higher levels of PA were associated with lower risk of stroke (p for trend = 0.016). The benefits of PA on obese and overweight breast cancer survivors were smaller than those in normal weight survivors. The frequency of moderate-to-vigorous physical activity (MVPA) showed a reverse J-curve association with CVD, and the best benefit occurred in the 3-4 times MVPA per week group (aHR 0.59, 95% CI 0.46-0.74). The study showed that even small amounts of PA may be beneficial in potentially decreasing the risk of CVD, CHD, and stroke in breast cancer survivors. Our result will be useful to prescribe and delivery exercise among long-term breast cancer survivors.

Abstract PS6-49: Intratumoral cytotoxic t-lymphocyte numbers and chemokine predict long-term survival of triple-negative breast cancer independently of tumor mutational burden

Abstract Background: Cytotoxic T-lymphocyte (CTL) infiltration into tumor is a positive prognostic factor in breast cancer. While high tumor mutation burden (TMB) is also considered as a predictor of tumor immunogenicity and response to immunotherapy. Triple-negative breast cancer (TNBC) has a higher TMB and accumulates more CTLs compared to other breast cancer subtypes. CTLs are identified by CD8 surface marker, which is encoded by CD8A gene. Granzyme B (GZMB) is a serine protease that is secreted by activated CTLs to induce apoptosis of the target cells. Chemokines, such as CXCL10 and CCL5 are key to the selective attraction of activated CTLs into tumors, as shown in multiple cancers. However, it remains unknown whether tumor infiltrating functional CTLs levels correlate with improved patient survival and are independent of TMB. In order to investigate it, we developed Functional Hotness Score (FHS) combining gene expressions of markers and attractants of activated CTL. Methods: Utilizing publicly available breast cancer cohorts, we established Functional Hotness Score (FHS), based on gene expression levels of CTL and chemokine markers in bulk tumors. The associations of FHS and breast cancer patient prognosis as well as distinct immunity markers were analyzed. Results: CD8, GZMB and CXCL10 combination resulted in the best prediction of the breas cancer patient prognosis. Thus, we established FHS based on the expression levels of these three genes. Breast cancer patients with the high-FHS tumors showed significantly better survival. FHS was lower in the metastatic breast cancers. Among breast cancer subtypes, triple-negative breast cancer (TNBC) showed the highest FHS. FHS predicted patient survival in hormone receptor (HR)-negative, especially TNBC, but not in HR-positive breast cancer. The high-FHS TNBCs showed not only higher CD8+ T cell infiltration, but also enhanced broader type-1 anti-cancer immunity. The patients with the high-FHS tumors showed better prognosis not only in high-TMB tumors but also in low-TMB TNBCs. The combination of high-TMB with high-FHS identified a unique subset of patients who do not recur over time. Conclusions: TNBCs with high-FHS based on the expression levels of CD8A, GZMB and CXCL10 showed improved prognosis with higher anti-cancer immunity regardless of TMB. FHS constitutes an independent prognostic marker of survival, particularly robust when combined with TMB in TNBCs. Citation Format: Eriko Katsuta, Li Yan, Mateusz Opyrchal, Pawel Kalinski, Kazuaki Takabe. Intratumoral cytotoxic t-lymphocyte numbers and chemokine predict long-term survival of triple-negative breast cancer independently of tumor mutational burden [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-49.

Potential effects of nutrition-based weight loss therapies in reversing obesity-related breast cancer epigenetic marks.

Obesity is a modifiable risk factor of breast cancer and epigenetic marks were proposed as a relevant mechanistic link. These mechanisms can be remodelled by modifying lifestyle factors and this fact could be useful in the treatment of obesity-related breast cancer. This review aimed to reveal the current evidence on the effects of differences in body composition and lifestyle factors on the risk, treatment, and survival of breast cancer with a focus on the effects of weight loss therapies based on different nutrients, bioactive compounds, and Mediterranean and ketogenic diets to counteract obesity-related breast cancer epigenetic marks. This review was framed on the most relevant and recently published articles and abstracts selected in PubMed using key words related to epigenetics, lifestyle, dietary habits, nutrients, bioactive compounds, ketone bodies, and weight loss treatments in obesity and breast cancer. Several studies have demonstrated that lifestyle interventions, including dietary modifications towards a healthy diet pattern, are effective therapies to prevent the onset of breast cancer and to improve the survival after treatment. These therapies reduce the main factors associated with obesity that are links between adiposity and cancer, including oxidative stress, inflammation and epigenetic mechanisms. However, although sufficient evidence exists regarding the effects of nutrients, dietary patterns, and weight loss therapies to prevent breast cancer or to improve survival, the effects of these strategies on the oncological treatment response were less studied. This review summarises the current scientific evidence regarding these nutritional strategies as adjuvant therapies in the management of obesity-related breast cancer by remodelling epigenetic marks related to carcinogenesis.

Comorbidity burden in long-term breast cancer survivors compared with a cohort of population-based controls from the MARIE study.

The number of elderly cancer survivors is growing because of increasing survival rates. A high comorbidity burden in the elderly can affect their quality of life and survival. The aim of this study was to examine whether breast cancer survivors and population-based controls have a different comorbidity burden after long-term follow-up. This study used data from a German breast cancer case-control study, which initially comprised 3813 breast cancer cases aged 50 to 74 years who were diagnosed between 2002 and 2005 and 7341 population-based controls. Participants were followed up in 2014/2016. A modified Charlson Comorbidity Index (mCCI) was calculated to quantify severe comorbidities. Negative binomial regression was performed to estimate rate ratios (RRs) with 95% confidence intervals (CIs) for the association between case-control status and mCCI (dependent variable) for the baseline population and for those who participated at follow-up, with adjustments made for relevant lifestyle factors. In total, 1925 cases and 3674 controls participated in the follow-up 12 years after recruitment. In the baseline population 35% had at least 1 comorbid condition.In long-term survivors this proportion was 52%. No difference was found in the mCCI between breast cancer cases and controls at baseline (RR, 1.05; 95% CI, 0.98-1.11) or between long-term survivors of the 2 groups at baseline (RR, 1.07; 95% CI, 0.97-1.18) or at follow-up (RR, 1.00; 95% CI, 0.91-1.10). The comorbidity burden of long-term breast cancer survivors and controls increased over time; however, it remained similar in both groups after 12 years of follow-up.

Identification of long-term survival-associated gene in breast cancer.

Breast cancer patients at the same stage may show different clinical prognoses or different therapeutic effects of systemic therapy. Differentially expressed genes of breast cancer were identified from GSE42568. Through survival, receiver operating characteristic (ROC) curve, random forest, GSVA and a Cox regression model analyses, genes were identified that could be associated with survival time in breast cancer. The molecular mechanism was identified by enrichment, GSEA, methylation and SNV analyses. Then, the expression of a key gene was verified by the TCGA dataset and RT-qPCR, Western blot, and immunohistochemistry. We identified 784 genes related to the 5-year overall survival time of breast cancer. Through ROC curve and random forest analysis, 10 prognostic genes were screened. These were integrated into a complex by GSVA, and high expression of the complex significantly promoted the recurrence-free survival of patients. In addition, key genes were related to immune and metabolic-related functions. Importantly, we identified methylation of MEX3A and TBC1D 9 and mutations events. Finally, the expression of UGCG was verified by the TCGA dataset and by experimental methods in our own samples. These results indicate that 10 genes may be potential biomarkers and therapeutic targets for long-term survival in breast cancer, especially UGCG.

The impact of fear of cancer recurrence on healthcare utilization among long-term breast cancer survivors recruited through ECOG-ACRIN trials.

To examine the relationship between fear of cancer recurrence (FCR) and healthcare utilization among long-term breast cancer survivors (BCS). In a cross-sectional survey study, 505 younger survivors (YS: ≤45 years) and 622 older survivors (OS: 55-70 years) 3-8 years from diagnosis completed a questionnaire assessing demographics, medical history, FCR, and healthcare utilization. Healthcare utilization consisted of breast cancer (BC) and non-BC-related routine and nonroutine utilization. YS had significantly higher FCR than OS (p < 0.01). Independent of age, FCR was significantly associated with all three types of BC-related utilization (p < 0.05). In the multivariate models, we found a significant, positive interaction effect between FCR and increased comorbidities on nonroutine BC appointments (p = 0.01) and BC-related emergency room visits (p = 0.03). Additionally, comorbidities were associated with non-BC-related utilization (p < 0.01), and nonwhites were more likely to utilize nonroutine resources, both BC and non-BC-related (p < 0.01). Increased FCR has been associated with hypervigilance among survivors and may lead to increased healthcare utilization. YS are at higher risk for increased FCR and psychosocial concerns, which may lead to overutilization. Providers should be aware that higher FCR may be related to increased use of healthcare resources and that these patients might be better served with supportive resources to increase quality of life and decrease inappropriate utilization. While this study provides increased evidence of the relationship between FCR and healthcare utilization, interventions are needed for survivors at risk to address unmet needs, especially as life expectancy increases among BCS.

Age‐specific prevalence and determinants of depression in long‐term breast cancer survivors compared to female population controls

BackgroundDepression is more prevalent in breast cancer (BC) survivors than in the general population. However, little is known about depression in long‐term survivors. Study objectives were: (1) to compare the age‐specific prevalence of depressive symptoms (a) in BC survivors vs female population controls, (b) in disease‐free BC survivors vs BC survivors with self‐reported recurrence vs controls, and (2) to explore determinants of depression in BC survivors.MethodsAbout 3010 BC survivors (stage I‐III, 5‐16 years post‐diagnosis), and 1005 population controls were recruited in German multi‐regional population‐based studies. Depression was assessed by the Geriatric Depression Scale‐15. Prevalence of mild/severe and severe depression only were estimated via logistic regression, controlling for age and education. Multinomial logistic regression was used to explore determinants of mild and severe depression.ResultsCompared with population controls, BC survivors were more likely to report mild/severe depression (30.4% vs 23.8%, p = .0003), adjusted for age and education. At all age groups <80 years, prevalence of both mild/severe and severe depression only was significantly higher in BC survivors, while BC survivors ≥80 years reported severe depression less frequently than controls. BC survivors with recurrence reported significantly higher prevalence of mild/severe depression than disease‐free survivors and controls, but prevalence in disease‐free survivors and controls was comparable. Age, income, living independently, recurrence, and BMI were significant determinants of mild depression in BC survivors. Age, education, employment, income, recurrence, and BMI were significant determinants of severe depression.ConclusionsLong‐term BC survivors <80 years report significantly higher prevalence of depressive symptoms than controls, which might be explained by recurrence and individual factors. The findings suggest that depression in BC survivors is common, and even more after BC recurrence. Clinicians should routinize screening and normalize referral to psychological care.

3LBA - Fatigue among long-term breast cancer survivors: a controlled cross-sectional study

3LBA - Fatigue among long-term breast cancer survivors: a controlled cross-sectional study

359 Poster - Evaluation of the use of primary and hospital care in long-term breast cancer survivors: A longitudinal study based on real-world data

359 Poster - Evaluation of the use of primary and hospital care in long-term breast cancer survivors: A longitudinal study based on real-world data

Symptoms in long-term breast cancer survivors: A cross-sectional study in primary care

PurposeVarious long-term symptoms can manifest after breast cancer treatment, but we wanted to clarify whether these are more frequent among long-term breast cancer survivors than matched controls and if they are associated with certain diagnoses. MethodsThis was a cross-sectional, population-based study of 350 breast cancer survivors treated with chemo- and/or radiotherapy ≥5 years (median 10) after diagnosis and 350 women without cancer matched by age and primary care physician. All women completed a questionnaire enquiring about symptoms, underwent echocardiography to assess the left ventricle ejection fraction, and completed the Hospital Anxiety and Depression Scale. Cardiovascular diseases were diagnosed from primary care records. In a multivariable logistic regression analysis, symptoms were adjusted for the long-term effects and compared between cohorts and within the survivor group. ResultsConcentration difficulties, forgetfulness, dizziness, and nocturia were more frequent among breast cancer survivors compared with controls, but differences could not be explained by cardiac dysfunction, cardiovascular diseases, depression, or anxiety. Intermittent claudication and appetite loss were more frequent among breast cancer survivors than controls and associated with cardiac dysfunction, depression, and anxiety. Breast cancer survivors treated with chemotherapy with/without radiotherapy were at significantly higher odds of forgetfulness and nocturia, but significantly lower odds of dizziness, compared with breast cancer survivors treated with radiotherapy alone. ConclusionsIntermittent claudication and appetite loss are common among breast cancer survivors and are associated with cardiac dysfunction and mood disorders. Other symptoms varied by whether the patient underwent chemotherapy with/without radiotherapy (forgetfulness and nocturia) radiotherapy alone (dizziness).

Use of real-world data to study health services utilisation and comorbidities in long-term breast cancer survivors (the SURBCAN study): study protocol for a longitudinal population-based cohort study

IntroductionBreast cancer has become a chronic disease due to survival improvement and the need to monitor the side effects of treatment and the disease itself. The aim of the SURBCAN...

Abstract 6616: Functional hotness score generated by representative functional cytotoxic T-lymphocytes predicts long-term survival of triple-negative breast cancer independently to the tumor mutational burden

Abstract Background: Cytotoxic T-lymphocytes (CTLs) infiltration in a bulk tumor is a positive prognostic factor in breast cancer. CTL recognition is believed to react to mutation-induced neoantigens, thus, higher tumor mutation burden (TMB) is considered as an important predictor of tumor immunogenicity and response to immunotherapy. Although majority of breast cancer have low tumor mutation burden (TMB), triple-negative breast cancer (TNBC) has higher TMB compared to other breast cancer subtypes. However, it is unclear if the prognostic value high CTL infiltration depends on the TMB as the primary driver of enhanced anti-cancer immunity or represents an independent prognostic marker which can be used as a complement to TMB to predict patients' outcomes. CTLs are identified by CD8 marker, is encoded by CD8A. Granzyme B (GZMB) is a serine protease that is secreted by functionally-active CTLs to induce apoptosis of the target cells. CXCL10 is a chemokine which selectively attracts activated CTLs into subsets of other cancers; but its role in breast cancer remains unknown. We investigated if TNBC infiltrated with high levels of functional CTLs, so called “hot tumors”, have improved survival independently of their TMB. Methods: Utilizing The Cancer Genome Atlas (TCGA) breast cancer cohort, we established Functional Hotness Score (FHS), based on the CD8A, GZMB and CXCL10 gene expression levels of bulk tumors. Total of 4149 breast cancer patients from publicly available multiple cohorts were analyzed to assess FHS and breast cancer patient prognosis as well as distinct immunity markers. Results: FHS predicted the breast cancer patient survival better than each consisting gene. The breast cancer patients with high FHS tumors showed significantly better survival in the testing cohort (TCGA), which was further confirmed in the validation cohort (METABRIC). FHS was higher in the primary breast cancer tissues with metastasis compared to that without metastasis in TCGA. Further, FHS was higher in the metastatic tumors compared to the primary tumors in GSE110590. Among breast cancer subtypes, TNBC showed highest FHS compared to other subtypes in testing TCGA, which was validated in the METABRIC cohort. The patients with high FHS tumor demonstrated significantly better long-term survival than that with low FHS only in the hormone receptor (HR)-negative breast cancers, but not in the HR-positive tumors. The high FHS TNBCs showed higher not only CD8-positive T cell infiltration, but also a broader type-1 anti-cancer immunity. To investigate if FHS predicts patient survival independent of TMB, the patients were divided into high and low TMB groups. Interestingly, the higher FHS patients showed better prognosis not only in the high TMB group but also in the low TMB among TNBC patients. The combination of high TMB with high FHS identified the unique subset of the patients who did not recur over time. Conclusion: In conclusion, TNBC with higher FHS based on the expression levels of CD8A, GZMB and CXCL10 showed improved prognosis with higher anti-cancer immunity regardless of TMB, and constituting an independent prognostic marker of survival, particularly when combined with TMB. Citation Format: Eriko Katsuta, Li Yan, Mateusz Opyrchal, Pawel Kalinski, Kazuaki Takabe. Functional hotness score generated by representative functional cytotoxic T-lymphocytes predicts long-term survival of triple-negative breast cancer independently to the tumor mutational burden [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6616.