Chemotherapy-treated Breast Cancer Patients Research Articles

Effect of mindfulness-based intervention on perceived stress among breast cancer patients undergoing chemotherapy

ABSTRACT Introduction: Breast cancer is the second most prevalent disease among women in India and one of the most dangerous and lethal. Chemotherapy-treated breast cancer patients may have perceived stress, which is defined as emotions of mental or physical exhaustion that make them feel angry or anxious. Mindfulness-based intervention (MBI) gives some ideas in line with the conventional mindfulness technique. Purposes: (i) To assess the effect of MBI on perceived stress among breast cancer patients undergoing chemotherapy. (ii) To determine the association between perceived stress with selected demographic variables among breast cancer patients undergoing chemotherapy. Methods: The current quantitative pre- and postexperimental study was carried out in two oncology departments of selected cancer hospitals, Bhubaneswar. A total number of 40 breast cancer patients of perceived stress receiving chemotherapy and data were gathered by using a self-structured socio-demographic proforma and a structured Perceived Stress Scale 10. The experimental group received MBI, and a posttest was conducted on the 17th day on both the groups after 10 days of the termination of intervention. This MBI was provided to breast cancer patients for five sessions over five days continuously, each session for 45 min with mindfulness breathing exercises, progressive muscle relaxation techniques, practising meditation, and guided imagery technique. Results: The study findings illustrated that reduction of perceived stress among female breast cancer patients undergoing chemotherapy with (t = 2.2463) (P = 0.0306) at the P < 0.05; furthermore, there is one socio-demographic variable which had association with perceived stress that is history of psychiatric illness (χ2 = 14.1176) (P = 0.0009) and others had no association with perceived stress. Conclusion: MBI was an effective therapy for reducing the perceived stress of breast cancer patients undergoing chemotherapy.

Stromal Type I Collagen in Breast Cancer: Correlation to Prognostic Biomarkers and Prediction of Chemotherapy Response

IntroductionFibrillar collagens accumulate in the breast cancer stroma and appear as poorly defined spiculated masses in mammography imaging. The prognostic value of tissue type I collagen remains elusive in treatment-naïve and chemotherapy-treated breast cancer patients. Here, type I collagen mRNA and protein expression were analysed in 2 large independent breast cancer cohorts. Levels were related to clinicopathological parameters, prognostic biomarkers, and outcome. MethodCOL1A1 mRNA expression was analysed in 2509 patients with breast cancer obtained from the cBioPortal database. Type I collagen protein expression was studied by immunohistochemistry in 1395 women diagnosed with early invasive breast cancer. ResultsLow COL1A1 mRNA and protein levels correlated with poor prognosis features, such as hormone receptor negativity, high histological grade, triple-negative subtype, node positivity, and tumour size. In unadjusted analysis, high stromal type I collagen protein expression was associated with improved overall survival (OS) (HR = 0.78, 95% CI = 0.61-0.99, p = .043) and trended towards improved breast cancer–specific survival (BCSS) (HR = 0.65, 95% CI = 0.42-1.01, P = 0.053), although these findings were lost after adjustment for other clinical variables. In unadjusted analysis, high expression of type I collagen was associated with better OS (HR = 0.70, 95% CI = 0.55-0.90, P = .006) and BCSS (HR = 0.55, 95% CI = 0.34-0.88, P = .014) among patients not receiving chemotherapy. Strikingly, the opposite was observed among patients receiving chemotherapy. There, high expression of type I collagen was instead associated with worse OS (HR = 1.83, 95% CI = 0.65-5.14, P = .25) and BCSS (HR = 1.72, 95% CI = 0.54-5.50, P = .357). ConclusionLow stromal type I collagen mRNA and protein expression are associated with unfavourable tumour characteristics in breast cancer. Stromal type I collagen might predict chemotherapy response.

Abstract B017: VCP extracts the chromatin remodeler SNF2H from nascent DNA to stabilize stressed replication forks

Abstract Valosin-containing protein (VCP) is an evolutionarily conserved AAA+ ATPase which plays pleiotropic roles in global proteostasis by extracting polyubiquitinated proteins from various cellular organelles and structures and facilitating their turnover. Our recent work demonstrated that nuclear VCP activity during DNA damage response specifically depends on ATM/ATR/DNA-PK-mediated Ser784 phosphorylation. Ser784phosphorylation increases VCP ability to facilitate chromatin-associated protein degradation and is required for DNA repair, checkpoint signaling, and cell survival. Clinically, high nuclear pSer784-VCP levels are significantly associated with poor survival outcome among chemotherapy-treated breast and pancreatic cancer patients. Thus, pSer784-VCP is a broadly important and therapeutically relevant genome stabilizer. Here, we focused specifically on the role of pSer784-VCP in DNA replication fork stability during stress, a known source of DNA damage if not properly regulated. By performing single-molecule DNA fiber analysis using human cell lines with genetic gain and loss-of-function of VCP, we observed that VCP protects nascent DNA from hydroxyurea (HU)-induced over-resection and this activity requires Ser784 phosphorylation. Using proximity ligation assay (PLA), we detected HU-induced pSer784-VCP on nascent DNA, suggesting that it may protect stressed forks by extracting functionally important regulators. Consistent with this theory, we detected an interaction of pSer784-VCP with SNF2H, a nucleosome-sliding enzyme which we recently found essential for nascent DNA over-resection at unprotected forks. In support of the hypothesis that SNF2H is a novel substrate of pSer784-VCP at stressed forks, we observed SNF2H retention on nascent DNA upon VCP knockdown in HU-treated cells, and the functional rescue of SNF2H retention by VCP re-expression requires Ser784phosphorylation. In support of their epistatic relationship, SNF2H depletion fully rescued fork over-resection caused by VCP loss. Similarly, blocking fork reversal by depleting SMARCAL1 or FBH1 also rescued fork over-resection caused by VCP loss. Importantly, mutating the ATPase activity of SNF2H abolished its ability to promote fork over-resection, suggesting that nucleosome remodeling by SNF2H underlies its effect on fork stability and may be a key molecular event enabling fork reversal upstream of fork degradation. Collectively, our data suggest that pSer784-VCP is a previously unrecognized stabilizer of stressed DNA replication forks, and it does so at least in part via its physical extraction of SNF2H from nascent DNA and the consequent attenuation of nucleosome remodeling needed for fork reversal and over-resection. More experiments are currently underway to further dissect the mechanistic aspects of this working model as well as to evaluate the potential of developing pSer784-VCP into a clinically relevant chemo-predictive biomarker and chemo-sensitizing target for different types of cancer. Citation Format: Jieya Shao, Mari Iwase, Rong Xu, Shuyang Lin. VCP extracts the chromatin remodeler SNF2H from nascent DNA to stabilize stressed replication forks [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B017.

How Asian Breast Cancer Patients Experience Unequal Incidence of Chemotherapy Side Effects: A Look at Ethnic Disparities in Febrile Neutropenia Rates.

The majority of published findings on chemotherapy-induced febrile neutropenia (FN) are restricted to three ethnic groups: Asians, Caucasians, and African Americans. In this two-part study, we examined FN incidence and risk factors in Chinese, Malay, and Indian chemotherapy-treated breast cancer (BC) patients. Hospital records or ICD codes were used to identify patients with FN. In both the Singapore Breast Cancer Cohort (SGBCC) and the Joint Breast Cancer Registry (JBCR), the time of the first FN from the start of chemotherapy was estimated using Cox regression. Multinomial regression was used to evaluate differences in various characteristics across ethnicities. FN was observed in 170 of 1014 patients in SGBCC. The Cox model showed that non-Chinese were at higher risk of developing FN (HRMalay [95% CI]:2.04 [1.44-2.88], p < 0.001; HRIndian:1.88 [1.11-3.18], p = 0.018). In JBCR, FN was observed in 965 of 7449 patients. Univariable Cox models identified ethnicity, a lower baseline absolute neutrophil count, non-luminal A proxy subtypes, and anthracycline-containing regimens as risk factors. Disparities across ethnicities' risk (HRMalay:1.29 [1.07-1.54], p = 0.006; HRIndian:1.50 [1.19-1.88], p < 0.001) remained significant even after further adjustments. Finally, an age-adjusted multinomial model showed that Malays (p = 0.006) and Indians (p = 0.009) were significantly more likely to develop multiple episodes of FN during treatment. Ethnic differences in chemotherapy-induced FN among BC patients exist. Further studies can focus on investigating pharmacogenetic differences across ethnicities.

Chemotherapy-Induced Toxicities and Their Associations with Clinical and Non-Clinical Factors among Breast Cancer Patients in Vietnam.

Understanding the burden and factors related to chemotherapy-induced toxicity is important in treatment planning for breast cancer patients. We conducted a prospective study among 396 newly diagnosed and chemotherapy-treated breast cancer patients recruited in two major cancer hospitals in northern Vietnam. Toxicities were captured through medical chart reviews and patient self-reports and graded using NCI CTCAE classification. Associations for sociodemographic and clinical factors with chemotherapy-induced toxicities during first-line chemotherapy were evaluated via multivariable logistic regression. Severe (i.e., grade ≥ 3) hematological (38.6%), and gastrointestinal (12.9%) toxicities were common. A pre-existing nephrological condition was significantly associated with the risk of severe hematological toxicity with adjusted odds ratios (OR) and 95% confidence intervals (CIs) of 2.30 (1.32-4.01). Patients living in rural areas had a lower risk of severe hematological toxicity (OR = 0.48; 95% CI, 0.30-0.77). Patients diagnosed with stage II and stage III-IV had a lower risk of severe gastrointestinal toxicity with ORs and 95% CIs of 0.26 (0.12-0.59) and 0.47 (0.20-1.10), respectively. Triple-negative/basal-like subtype was associated with a higher risk of severe hematological (OR = 3.15; 95% CI, 1.56-6.34) and gastrointestinal toxicities (OR = 3.60; 95% CI, 1.45-8.95) comparing to hormone receptor (HR)-positive HER2-negative subtype. Further research investigating underlying mechanisms would facilitate the development and delivery of personalized treatment and care plans.

197P Long-term effects of physical exercise on self-reported cognitive function, fatigue, and quality of life in chemotherapy-treated breast cancer patients

In the randomized controlled Physical Activity and Memory (PAM) study, we found beneficial effects immediately after a 6-month supervised exercise program on self-reported cognitive complaints, fatigue, and quality of life (QoL) in chemotherapy-exposed breast cancer patients with cognitive complaints and tested cognitive problems. The present study assessed whether these effects sustained till one year after study completion.

Abstract P4-07-28: Early relapse and predictors of relapse-free survival in neoadjuvant chemotherapy-treated breast cancer patients

Abstract RationaleNeoadjuvant chemotherapy (NAC) for the treatment of early and locally advanced breast cancer is shown to cause effective tumour shrinkage, allowing breast conserving surgery. However, rates of recurrence remain high following surgical excision of NAC-treated breast tumours. We investigated relapse-free survival (RFS) in NAC-treated breast cancer patients; the primary aim of this study was to estimate probability of early relapse (&amp;lt;5 years) and identify possible predictor variables. MethodsWe retrospectively reviewed NAC-treated breast cancer patients diagnosed between January 2013 and August 2018 at the Royal Cornwall Hospital, UK. Patients met inclusion criteria with &amp;gt;3 cycles of NAC, surgery and follow-up &amp;gt;1 year. Demographic, histopathological and surgical data were collected including age, TNM classification, tumour histology, breast cancer immunohistochemical marker receptor status (ER, PR, HER2), NAC dose, adjuvant radiotherapy, type of breast and nodal surgery, pathologic response to NAC, number of positive lymph nodes (LN) at surgical removal and lymph node ratio (LNR). Tumour histology was categorised by inflammatory versus non-inflammatory. TNM classification was used for tumour staging. TNM nodal classification was categorised as N0 or N1 according to axillary LN cytology. LN classification data was missing for patients with inconclusive LN status at diagnosis. LNR was calculated as the ratio of positive LN to total number of LN removed at surgery. NAC response was categorised as pathologic complete (pCR) or incomplete (no-pCR). Kaplan-Meier method was used to compare survival functions for categorical variables. The Cox proportional hazards model was used at univariate and multivariate analysis for predictor variables that satisfied the proportional hazards assumption, to calculate hazard ratios for RFS. p-values &amp;lt;0.05 were taken as statistically significant. Results165 of 190 women were eligible for analysis. Median (IQR) age at diagnosis was 51.7 years (45.5-60.3). 68 patients (41.2%) achieved pCR following NAC and 147 (89.1%) received adjuvant RT. 30 relapses (18.2%) were recorded during follow-up, of which 24 (80%) were distant metastases. The Kaplan-Meier survival function estimated a 25% (95% CI, 17-36) probability of relapse by year five post-surgery. At univariate Cox analysis, RFS was associated with fewer positive LN (p = 0.001), lower LNR (p &amp;lt; 0.001) and TNM node classification N0 at diagnosis (p &amp;lt; 0.001). Table 1 below shows the results of multivariate Cox proportional hazards regression. Small sample size might conceal statistical significance of some covariates. ConclusionsOver 1 in 4 NAC-treated breast cancer patients relapsed within 5 years of surgery, usually with distant metastases. At univariate analysis, relapse-free survival (RFS) was individually associated with decreased LNR, fewer positive LN and TNM node classification N0. LNR remained a significant predictor of RFS at multivariate analysis with risk of relapse for a LNR of 1, 9-fold higher than a LNR of 0. Age, tumour histology, HER2 receptor status, TNM tumour classification, NAC dose and response to NAC had no significant association with RFS in this sample size. Risk FactorSubjectsHazard Ratio (95% CI)p-valueAge1651.042 (0.998 - 1.088)0.064Tumour histology (inflammatory = 1, other = 0)1651.268 (0.302 - 5.331)0.746HER2 receptor status (HER2+ = 1, HER2- = 0)1651.217 (0.357 - 4.150)0.754TNM tumour classification (T3-4 = 1, T1-2 = 0)1650.852 (0.298 - 2.442)0.766TNM node classification (N1 = 1, N0 = 0)1021.684 (0.428 - 6.622)0.455NAC dose (full dose = 1, reduced dose = 0)1651.091 (0.393 - 3.028)0.866NAC response in breast (pCR = 1, no-pCR = 0)1650.696 (0.199 - 2.442)0.572Lymph node ratio1649.426 (2.061 - 43.099)0.004 Citation Format: Natalie Martin, Julia Pasztorova, Isabella Hibell, Duncan Wheatley. Early relapse and predictors of relapse-free survival in neoadjuvant chemotherapy-treated breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-28.

Neuroinflammation and Its Association with Cognition, Neuronal Markers and Peripheral Inflammation after Chemotherapy for Breast Cancer.

Simple SummaryUp to 70% of chemotherapy-treated patients experience problems with memory and concentration, potentially caused by direct and indirect neurotoxicity, such as (neuro-)inflammatory processes. Can neuroinflammation changes be detected in chemotherapy-treated patients with breast cancer using translocator protein [18F]DPA714 simultaneous positron emission tomographic- and magnetic resonance imaging? Moreover, what is the association with clinical biomarkers? In a study including 19 chemotherapy-treated breast cancer patients, 18 chemotherapy-naïve and 37 healthy controls, we found significant relative glial overexpression in parietal and occipital brain regions in chemotherapy-treated patients compared to controls, which were associated with cognitive abnormalities and markers of neuronal survival. Shortly after ending chemotherapy, changes in brain neuroinflammation seem to occur, possibly contributing to the cognitive decline seen in breast cancer patients. Additionally, blood levels of an axonal damage marker were 20-fold higher in chemotherapy-treated patients, providing evidence for its use as a biomarker to assess neurotoxic effects of anticancer chemotherapies.To uncover mechanisms underlying chemotherapy-induced cognitive impairment in breast cancer, we studied new biomarkers of neuroinflammation and neuronal survival. This cohort study included 74 women (47 ± 10 years) from 22 October 2017 until 20 August 2020. Nineteen chemotherapy-treated and 18 chemotherapy-naïve patients with breast cancer were assessed one month after the completion of surgery and/or chemotherapy, and 37 healthy controls were included. Assessments included neuropsychological testing, questionnaires, blood sampling for 17 inflammatory and two neuronal survival markers (neurofilament light-chain (NfL), and brain-derived neurotrophic factor (BDNF) and PET-MR neuroimaging. To investigate neuroinflammation, translocator protein (TSPO) [18F]DPA714-PET-MR was acquired for 15 participants per group, and evaluated by volume of distribution normalized to the cerebellum. Chemotherapy-treated patients showed higher TSPO expression, indicative for neuroinflammation, in the occipital and parietal lobe when compared to healthy controls or chemotherapy-naïve patients. After partial-volume correction, differences with healthy controls persisted (pFWE < 0.05). Additionally, compared to healthy- or chemotherapy-naïve controls, cognitive impairment (17–22%) and altered levels in blood markers (F ≥ 3.7, p ≤ 0.031) were found in chemotherapy-treated patients. NfL, an axonal damage marker, was particularly sensitive in differentiating groups (F = 105, p = 4.2 × 10 −21), with levels 20-fold higher in chemotherapy-treated patients. Lastly, in chemotherapy-treated patients alone, higher local TSPO expression was associated with worse cognitive performance, higher blood levels of BDNF/NfL, and decreased fiber cross-section in the corpus callosum (pFWE < 0.05). These findings suggest that increased neuroinflammation is associated with chemotherapy-related cognitive impairment in breast cancer. Additionally, NfL could be a useful biomarker to assess neurotoxic effects of anticancer chemotherapies.

Increased resting-state cerebellar-cortical connectivity in breast cancer survivors with cognitive complaints after chemotherapy

Cognitive complaints after chemotherapy are common in breast cancer patients, but the neural bases for these complaints remain unclear. This pilot study explored resting-state functional connectivity (FC) as a marker of subtle cognitive changes in breast cancer patients who experience cognitive complaints. Chemotherapy-treated (n = 20, at least 6 months off therapy) and untreated (n = 17, disease-control) female breast cancer patients with cognitive complaints and healthy controls (n = 20) were recruited. The FC of the right dorsolateral prefrontal cortex was calculated, and any correlations between this FC and neuropsychological assessments were determined. Chemotherapy-treated patients with cognitive complaints displayed increased FC between the right dorsolateral prefrontal cortex and both the contralateral cerebellar lobule VII and the cerebellar vermis XI, compared to the disease-control and healthy-control groups, despite unimpaired neuropsychological performance. The increased FC was negatively correlated with executive function and attention in breast cancer survivors with cognitive complaints. Our pilot study findings provide evidence that cerebellar-cortical FC changes may be a pathophysiological basis for chemotherapy-related cognitive complaints. In addition, the FC changes have the potential to reflect minor or compensated cognitive function impairment in breast cancer patients.

Network-level functional connectivity alterations in chemotherapy treated breast cancer patients: a longitudinal resting state functional MRI study

BackgroundPrevious studies have found abnormal structural and functional brain alterations in breast cancer survivors undergoing chemotherapy. However, the network-level brain changes following chemotherapy remain unknown. The purpose of this study was to investigate the dynamic changes of large-scale within- and between-network functional connectivity in chemotherapy-treated breast cancer patients.MethodsSeventeen breast cancer patients were evaluated with resting state functional MRI (rs-fMRI), neuropsychological tests and blood examination before postoperative chemotherapy (t0), one week after completing chemotherapy (t1) and six months after completing chemotherapy (t2). Nineteen age- and education level-matched healthy controls (HC) were also recruited. Independent components analysis (ICA) was performed to assess network component using rs-fMRI data. The functional network changes were then correlated with cognitive assessment scores and blood biochemical indexes.ResultsOne-way repeated measures ANOVA revealed significantly changed within-network functional connectivity in the anterior and posterior default mode network (ADMN and PDMN), left and right frontoparietal network (LFPN and RFPN), visual network and self-referential network. Post-hoc test showed that decreased within-network functional connectivity in ADMN, PDMN, LFPN, RFPN, SRN and central network one week after chemotherapy and increased six months after chemotherapy (all P < 0.05). As for the between-network functional connectivity, the PDMN- sensorimotor network connectivity showed the same tendency. Most of these within- and between-network functional connectivity changes were negatively associated with blood biochemical indexes and cognitive assessment scores (all P < 0.05).ConclusionsThese results indicated that chemotherapy may induce widespread abnormalities in resting state networks, which may serve as a potential biomarker of chemotherapy related cognitive impairment, providing insights for further functional recovery treatment.

Circulating tumour cells as prognosis predictive markers of neoadjuvant chemotherapy-treated breast cancer patients

In this study, we detected and measured the count of circulating tumour cells (CTCs) in breast cancer (BC) patients who were treated by neoadjuvant chemotherapy (NAC) in order to assess the clinical validity of CTCs. A total of 96 patients with locally advanced BC and who were treated by NAC were enrolled in this study. The CTC count in the peripheral blood was estimated by negative enrichment-fluorescence in situ hybridization before and after NAC. The clinicopathological data of the patients were recorded. CTCs were detected in 59 of the 96 patients with BC before NAC. Particularly, the detection rate of CTCs was significantly lower in human epidermal growth factor receptor-2 (HER-2)-negative patients than in HER-2-positive patients. CTCs were significantly fewer after NAC than before NAC. The CTC-detection sensitivity in the NAC efficacy evaluation was 75.5% (40/53), while the specificity was 72.1% (31/43). The CTC consistency analysis with clinical effects (Response Evaluation Criteria in Solid Tumors Version 1.1 Standard) was described as moderate (kappa = 0.476, P < 0.001). Thus, our findings suggest that CTC detection is a potential new approach to assess the efficacy of NAC.

Phospho-Ser784-VCP Is Required for DNA Damage Response and Is Associated with Poor Prognosis of Chemotherapy-Treated Breast Cancer

Spatiotemporal protein reorganization at DNA damage sites induced by genotoxic chemotherapies is crucial for DNA damage response (DDR), which influences treatment response by directing cancer cell fate. This process is orchestrated by valosin-containing protein (VCP), an AAA+ ATPase that extracts polyubiquinated chromatin proteins and facilitates their turnover. However, because of the essential and pleiotropic effects of VCP in global proteostasis, it remains challenging practically to understand and target its DDR-specific functions. We describe a DNA-damage-induced phosphorylation event (Ser784), which selectively enhances chromatin-associated protein degradation mediated by VCP and is required for DNA repair, signaling, and cell survival. These functional effects of Ser784 phosphorylation on DDR correlate with a decrease in VCP association with chromatin, cofactors NPL4/UFD1, and polyubiquitinated substrates. Clinically, high phospho-Ser784-VCP levels are significantly associated with poor outcome among chemotherapy-treated breast cancer patients. Thus, Ser784 phosphorylation is a DDR-specific enhancer of VCP function and a potential predictive biomarker for chemotherapy treatments.

Cumulative incidence of chemotherapy-induced cardiotoxicity during a 2-year follow-up period in breast cancer patients.

Cardiotoxicities are adverse effects often reported in chemotherapy-treated breast cancer patients. This study evaluated the potential risk factors and cumulative incidence of doxorubicin-induced cardiotoxicity in Korean breast cancer patients. We retrospectively analyzed the data of 613 breast cancer patients who underwent a multigated acquisition (MUGA) scan or echocardiography prior to chemotherapy and at least one post-chemotherapy follow-up MUGA scan/echocardiography between 2007 and 2016 at National Cancer Center, Korea. The Cox proportional hazards models were used to evaluate cardiotoxicity risks. Competing risks analyses were performed to estimate cumulative incidence of cardiotoxicity. Risk factors associated with cardiotoxicity within 2years of doxorubicin administration included age [adjusted hazard ratio (aHR) = 1.02, 95% confidence interval (CI) 1.00-1.04; p = 0.05], metastasis (aHR = 2.66; 95% CI 1.36-5.20; p < 0.01), and concomitant trastuzumab (aHR = 4.08; 95% CI 2.31-7.21; p < 0.01). The cumulative incidence of patients with cardiotoxicity was 6.1% at 2years (without substantial change from about 9months)and 20.2% at 2years (without substantial change from about 15months) after initiation of doxorubicin-containing therapy without and with trastuzumab, respectively. Susceptibility to chemotherapy-induced cardiotoxicity within 2years of doxorubicin initiation in breast cancer patients was elevated with old age, metastasis, and concomitant trastuzumab. Regular imaging monitoring at least up to 9months after doxorubicin initiation in patients treated without concomitant trastuzumab, and 15months in patients treated with concomitant trastuzumab, is needed for early detection of chemotherapy-induced cardiotoxicity.

Long-Term Favorable Effects of Physical Exercise on Burdensome Symptoms in the OptiTrain Breast Cancer Randomized Controlled Trial.

Purpose: We evaluate longitudinal changes in symptom clusters and core burdensome symptoms in breast cancer patients who participated in the OptiTrain trial. Methods: 240 women were randomized to 16 weeks of supervised exercise (RT-HIIT or AT-HIIT) or usual care (UC) during adjuvant chemotherapy. Symptom clusters were composed using the Memorial Symptom Assessment Scale (MSAS), assessed at baseline, 16 weeks and 12 months later. Three symptom clusters were formed. Results: Three symptom clusters were identified: “emotional,” “treatment-related toxicity,” and “physical,” with core burdensome symptoms present over time. At 16 weeks, the reported burdens of “feeling sad” (RT-HIIT vs UC: effect size [ES] = −0.69; AT-HIIT vs UC: ES = −0.56) and “feeling irritable” (ES = −0.41 RT-HIIT; ES = −0.31 AT-HIIT) were significantly lower in both intervention groups compared with UC. At 12 months, the AT-HIIT group continued to have significantly lower scores for the core burdensome symptoms “feeling sad” (ES = −0.44), “feeling irritable” (ES = −0.44), and “changes in the way food tastes” (ES = −0.53) compared with UC. No between-group differences were found for physical symptoms. Conclusion: We identified 3 symptom clusters in breast cancer patients during and after adjuvant chemotherapy, composed of “emotional,” “treatment-related toxicity,” and “physical” symptoms. After treatment completion up to 12 months post-baseline, patients in the physical exercise groups reported lower symptom burden scores for emotional symptoms, compared with UC. Our findings indicate a preserved and long-term beneficial effect of physical exercise on self-reported emotional well-being in chemotherapy-treated breast cancer patients.

Assessment of Gene Expression Level of ATP Binding Cassette G Member 2 (ABCG2) Transporter in Newly Diagnosed Breast Cancer Patients Receiving Adjuvant Chemotherapy

The efficacy of cancer chemotherapy is limited by cellular mechanisms of resistance that result in increased drug efflux of chemotherapeutic agents thereby reducing intracellular drug levels and causing drug resistance. Overexpression of some members of ATP binding cassette transporter superfamily, including ATP binding cassette G member 2 (ABCG2), which mediates energy-dependent transport of drugs out of the cells against concentration gradient, is one of the major mechanisms responsible for multidrug resistance in the treatment of breast cancer. In the current study, the expression of ABCG2 mRNA gene was evaluated in the peripheral blood of newly diagnosed breast cancer (NDBC) patients immediately before surgical resection of the breast and in extirpated breast tumors, then sequentially in the blood of patients after receiving three and six cycles of chemotherapy. Compared to normal breast, cancerous specimens expressed higher levels of ABCG2 gene expression (p&lt;0.001). In addition, a gradual significant increase in the expression of peripheral blood ABCG2 gene of NDBC patients among different treatment periods was recorded. Furthermore, a significant positive correlation between peripheral blood ABCG2 gene expression of NDBC patients receiving chemotherapy and disease progression was found. In conclusion, assessment of ABCG2 gene expression may be a prerequisite in evaluating the effectiveness of chemotherapy-treated breast cancer patients.

Cardiotoxicity and Cardiac Monitoring Among Chemotherapy-Treated Breast Cancer Patients

ObjectivesThis study sought to determine the rate of chemotherapy-related cardiotoxicity and to estimate adherence to recommendations for cardiac monitoring among breast cancer patients treated with chemotherapy. BackgroundHeart failure (HF) is a known complication associated with cancer therapies. Little is known regarding the rate of chemotherapy-related cardiotoxicity and adherence to recommendations for cardiac monitoring among chemotherapy-treated breast cancer patients. MethodsPatients >18 years of age with a diagnosis of nonmetastatic invasive breast cancer between 2009 and 2014, treated with chemotherapy within 6 months of their diagnosis, were identified in the Truven Health MarketScan (IBM Watson Health, Cambridge, Massachusetts) database. HF, comorbidities, and treatment details were identified using diagnosis and billing codes. Analyses included descriptive statistics, Cox proportional hazard regression, and logistic regression. ResultsA total of 16,456 patients were included; the median age was 56 years old. Cardiotoxicity was identified in 4.2% of patients. Therapy with trastuzumab (hazard ratio [HR]: 2.01; 95% confidence interval [CI]: 1.72 to 2.36) and anthracyclines (HR: 1.53; 95% CI: 1.30 to 1.80), Deyo comorbidity scores (HR: 1.38; 95% CI: 1.15 to 1.66; HR: 2.47; 95% CI: 1.94 to 3.15 for scores of 1 and ≥2, respectively), hypertension (HR: 1.28, 95% CI: 1.09 to 1.51), and valve disease (HR: 1.93; 95% CI: 1.48 to 2.51) were associated with an increased risk of cardiotoxicity. Patients ≤35 years of age (HR: 0.37; 95% CI: 0.19 to 0.72) and 36 to 49 years of age (HR: 0.49; 95% CI: 0.38 to 0.62) were less likely to have cardiotoxicity than patients 65 years of age and older. Among 4,325 patients treated with trastuzumab, guideline-adherent cardiac monitoring was identified in 46.2% of patients. Therapies using anthracyclines (odds ratio [OR]: 1.58; 95% CI: 1.35 to 1.87), taxanes (OR: 1.63; 95% CI: 1.27 to 2.08), and radiation (OR: 1.22; 95% CI: 1.08 to 1.39) were associated with guideline-adherent monitoring. ConclusionsHF is an uncommon complication of breast cancer therapies. The risk was higher among patients treated with trastuzumab or anthracyclines and lower in younger patients. Cardiac monitoring among trastuzumab-treated patients should be a priority among high-risk patients and in the presence of comorbidities or other chemotherapies such as those using anthracyclines.

Relation of polymorphism C1236T and C3435T in ABCB1 gene with bone marrow suppression in chemotherapy-treated breast cancer patients

ABCB1 is agene that encoded P-glycoprotein (P-gp), a transmembrane active efflux pump for a variety of carcinogens and cytostatics.ABCB1 polymorphisms C1236T and C3435T contribute to the variability oftherapeutic outcome and side effects.The present study was conducted to investigatethe relation of C1236T and C3435T polymorphisms in ABCB1 gene with bone marrow suppression in breast cancer patients treated withchemotherapy72 Indonesian womens isolated DNA sampleswere amplified using the PCR method. The analysis process of ABCB1 C1236T and C3435T polymorphism was by using thePCR-RFLP method. The frequencies of ABCB1 C1236T genotype for homozygous CC,heterozygous CT and variant TT was 11(15.28%), 42(58.33%), 19(26.39%), respectively. No associationwas between ABCB1 C1236T and C3435T polymorphisms in both individually and haplotypes with bone marrow suppression event (p > 0.05). There was no specific deviation of allele and genotype frequency from Hardy-Weinberg Equilibrium. There was a linkage between heterozygous CT-heterozygous CT in position 1236 and 3435 within 25 people (35%).

Abstract P2-01-01: Trajectory patterns of circulating tumor cells (CTC) in chemotherapy-treated metastatic breast cancer (MBC) patients predict poor clinical outcomes: CALGB 40502 (Alliance)/NCCTG N063H study

Abstract Little is known about the dynamics of CTCs during treatment and its clinical significance. We examined the predictive utility of serial CTC analysis in ER+HER2- MBC patients (pts) treated with chemotherapy in the CALGB 40502/NCCTG N063H study, a randomized phase III trial of weekly paclitaxel compared to weekly nanoparticle albumin bound nab-paclitaxel or ixabepilone +/- bevacizumab as first-line therapy (ClinicalTrials.gov Identifier: NCT00785291, Support: U10CA180821, U10CA180882). Methods: Of the 783 pts treated, 469 had ≥3 serial blood samples (including baseline) successfully analyzed for CTCs by CellSearch® and were included in this analysis (n=2,202). Samples with ≥5 CTCs per 7.5 mLs of blood were considered CTC+. The prognostic and predictive performance of baseline CTCs (bCTC) and CTC status from baseline to cycle 2 (b2CTC) were compared to a novel latent mixture model classification based on trajectory of CTCs (tCTC). Akaike Information Criterion (AIC) was used to select the model (bCTC vs b2CTC vs tCTC) that best predicts overall survival (OS), progression-free survival (PFS), and time-to-treatment failure (TTF). Results: 53% of the pts were CTC+ at baseline. b2CTC status changed in 36% of the pts, most of whom were CTC+CTC- (35%), and very few CTC-CTC+ (1%); the rest of the pts did not experience a change in b2CTC status (46% CTC-CTC- and 19% CTC+CTC+). Mixture model analysis revealed 4 groups of pts that show distinct tCTC patterns over the course of treatment: consitently very low/undectectable CTCs (tCTCneg, 56%), low (tCTClo, 24%), intermediate (tCTCmid, 15%), or high (tCTChi, 5%). bCTC, b2CTC, and tCTC were significantly correlated with tumor subtype (all p &amp;lt;0.0022) and presence of bone metastasis (all p &amp;lt;0.0001). Multivariate analysis showed that pts who were CTC+ at baseline, and those whose b2CTC status remained positive (CTC+CTC+) had significantly reduced OS, PFS and TTF. OSPFSTTFModelsHR (95% CI)p-valueHR (95% CI)p-valueHR (95% CI)p-valuebCTC (vs CTC-) → CTC+2.5(1.8-3.3)&amp;lt;0.00011.6(1.3-2.0)&amp;lt;0.00011.3(1.1-1.6)0.0046b2CTC (vs CTC+CTC-) → CTC-CTC+1.6(0.5-5.4)0.41491.6(0.6-4.5)0.39051.6(0.6-4.3)0.3961→ CTC+CTC+2.7(1.9-3.8)&amp;lt;0.00011.8(1.4-2.5)&amp;lt;0.00011.8(1.3-2.4)&amp;lt;0.0001→ CTC-CTC-0.5(0.4-0.8)0.00020.8(0.6-0.9)0.01600.9(0.7-1.1)0.2771tCTC (vs tCTCneg) → tCTClo2.6(1.9-3.7)&amp;lt;0.00011.9(1.4-2.4)&amp;lt;0.00010.9(0.7-1.1)0.0033→ tCTCmid5.3(3.6-8.0)&amp;lt;0.00012.5(1.8-3.4)&amp;lt;0.00011.8(1.4-2.5)0.0001→ tCTChi10.8(6.1-19)&amp;lt;0.00013.0(1.8-5.0)&amp;lt;0.00012.3(1.4-3.7)0.0009CTC- (&amp;lt;5 CTCs per 7.5 mLs); CTC+ (≥5 CTCs per 7.5 mLs) Pts with tCTClo, tCTCmid and tCTChi had significantly shorter OS, PFS and TTF compared to those with tCTCneg. After adjustment for potential confounders, AIC analysis revealed that the tCTC model best predicts OS and PFS, while b2CTC best predicts TTF. AIC Score*ModelsOSPFSTTFbCTC243240514199b2CTC240540384186tCTC237940264188*The lowest AIC score indicates the best model. Conclusions: Analysis of CTC trajectory patterns identified pts with poor outcome who could potentially benefit from more effective treatment. Validation in independent cohorts is warranted to confirm the findings in this study. Citation Format: Magbanua MJ, Hendrix L, Hyslop T, Barry WT, Winer EP, Hudis C, Toppmeyer D, Burnstein H, Qadir M, Ma C, Scott JH, Park JW, Rugo HS. Trajectory patterns of circulating tumor cells (CTC) in chemotherapy-treated metastatic breast cancer (MBC) patients predict poor clinical outcomes: CALGB 40502 (Alliance)/NCCTG N063H study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-01-01.

Altered network efficiency of functional brain networks in patients with breast cancer after chemotherapy.

ObjectiveTo investigate the topological organization of functional brain networks in chemotherapy-treated breast cancer (BC) patients with source memory impairment.MethodsTwenty-eight patients with BCfollowingchemotherapyand40age-and education-matched healthy controls (HCs) were recruited in the current study. All participants underwent source memory tests and resting-state functional MRI scans. Individual whole-brain functional brain networks were constructed and analyzed using graph-based network approaches.ResultsCompared with the HCs, the BC patients showed lower scores in the source memory tests (P < 0.001).Graph-based analyses revealed that the patients showed higher absolute global and local efficiency (both P < 0.01) but lower normalized global and normalized local efficiency (both P< 0.001) compared with the HCs. Locally, several prefrontal, occipital, and parietal regions exhibited higher nodal efficiency and functional connectivity in the patients(P< 0.05, corrected). Finally, positive correlations were observed between normalized global efficiency and Mini-Mental State Examination scores (r = 0.398, P = 0.036) and between normalized local efficiency and the source memory scores (r = 0.497, P = 0.01) in the patients.ConclusionChemotherapy-treated BC is associated with abnormal organization of large-scale functional brain networks, which could account for source memory dysfunction in patients with BC.

ADIPOQ/adiponectin induces cytotoxic autophagy in breast cancer cells through STK11/LKB1-mediated activation of the AMPK-ULK1 axis

ABSTRACT ADIPOQ/adiponectin, an adipocytokine secreted by adipocytes in the breast tumor microenvironment, negatively regulates cancer cell growth hence increased levels of ADIPOQ/adiponectin are associated with decreased breast cancer growth. However, its mechanisms of action remain largely elusive. We report that ADIPOQ/adiponectin induces a robust accumulation of autophagosomes, increases MAP1LC3B-II/LC3B-II and decreases SQSTM1/p62 in breast cancer cells. ADIPOQ/adiponectin-treated cells and xenografts exhibit increased expression of autophagy-related proteins. LysoTracker Red-staining and tandem-mCherry-GFP-LC3B assay show that fusion of autophagosomes and lysosomes is augmented upon ADIPOQ/adiponectin treatment. ADIPOQ/adiponectin significantly inhibits breast cancer growth and induces apoptosis both in vitro and in vivo, and these events are preceded by macroautophagy/autophagy, which is integral for ADIPOQ/adiponectin-mediated cell death. Accordingly, blunting autophagosome formation, blocking autophagosome-lysosome fusion or genetic-knockout of BECN1/Beclin1 and ATG7 effectively impedes ADIPOQ/adiponectin induced growth-inhibition and apoptosis-induction. Mechanistic studies show that ADIPOQ/adiponectin reduces intracellular ATP levels and increases PRKAA1 phosphorylation leading to ULK1 activation. AMPK-inhibition abrogates ADIPOQ/adiponectin-induced ULK1-activation, LC3B-turnover and SQSTM1/p62-degradation while AMPK-activation potentiates ADIPOQ/adiponectin's effects. Further, ADIPOQ/adiponectin-mediated AMPK-activation and autophagy-induction are regulated by upstream master-kinase STK11/LKB1, which is a key node in antitumor function of ADIPOQ/adiponectin as STK11/LKB1-knockout abrogates ADIPOQ/adiponectin-mediated inhibition of breast tumorigenesis and molecular analyses of tumors corroborate in vitro mechanistic findings. ADIPOQ/adiponectin increases the efficacy of chemotherapeutic agents. Notably, high expression of ADIPOQ receptor ADIPOR2, ADIPOQ/adiponectin and BECN1 significantly correlates with increased overall survival in chemotherapy-treated breast cancer patients. Collectively, these data uncover that ADIPOQ/adiponectin induces autophagic cell death in breast cancer and provide in vitro and in vivo evidence for the integral role of STK11/LKB1-AMPK-ULK1 axis in ADIPOQ/adiponectin-mediated cytotoxic autophagy.