Breast Cancer Events Research Articles

Recreational Physical Activity and Outcomes After Breast Cancer in Women at High Familial Risk

BackgroundRecreational physical activity (RPA) is associated with improved survival after breast cancer (BC) in average-risk women, but evidence is limited for women who are at increased familial risk because of a BC family history or BRCA1 and BRCA2 pathogenic variants (BRCA1/2 PVs).MethodsWe estimated associations of RPA (self-reported average hours per week within 3 years of BC diagnosis) with all-cause mortality and second BC events (recurrence or new primary) after first invasive BC in women in the Prospective Family Study Cohort (n = 4610, diagnosed 1993-2011, aged 22-79 years at diagnosis). We fitted Cox proportional hazards regression models adjusted for age at diagnosis, demographics, and lifestyle factors. We tested for multiplicative interactions (Wald test statistic for cross-product terms) and additive interactions (relative excess risk due to interaction) by age at diagnosis, body mass index, estrogen receptor status, stage at diagnosis, BRCA1/2 PVs, and familial risk score estimated from multigenerational pedigree data. Statistical tests were 2-sided.ResultsWe observed 1212 deaths and 473 second BC events over a median follow-up from study enrollment of 11.0 and 10.5 years, respectively. After adjusting for covariates, RPA (any vs none) was associated with lower all-cause mortality of 16.1% (95% confidence interval [CI] = 2.4% to 27.9%) overall, 11.8% (95% CI = -3.6% to 24.9%) in women without BRCA1/2 PVs, and 47.5% (95% CI = 17.4% to 66.6%) in women with BRCA1/2 PVs (RPA*BRCA1/2 multiplicative interaction P = .005; relative excess risk due to interaction = 0.87, 95% CI = 0.01 to 1.74). RPA was not associated with risk of second BC events.ConclusionFindings support that RPA is associated with lower all-cause mortality in women with BC, particularly in women with BRCA1/2 PVs.

Expression profile of tumour suppressor protein p53 and its regulator MDM2 in a cohort of breast cancer patients in a Tertiary Hospital in Ghana.

BackgroundInactivation or mutation of the tumour suppressor gene p53 or its regulator mouse double minute 2 (MDM2) is the commonest event in breast cancer. These altered genes usually express abnormally high levels of their proteins in many carcinomas. The phenotypic expression of p53 and MDM2 in breast cancer cases in our setting is not known. This study investigated the expression of the tumour suppressor protein p53 and its regulator MDM2, using immunohistochemistry in a Ghana breast cancer cohort.MethodA 9-year retrospective cross-sectional study on archived tissue blocks–formalin fixed paraffin embedded tissue (FFPE) was carried out. Demographic data were abstracted. Based on complete clinical data and availability of FFPE archived blocks 203 cases were selected for tissue micro array (TMA) construction. The TMA sections were subjected to immunohistochemistry (IHC) (ER, PR, HER2, p53, and MDM2). Expression of p53 and MDM2 were related to grade and molecular subtypes.ResultsThe age ranged from 17 to 92 years (mean = 49.34 ± 13.74). Most of the cases were high grade; grade II (34.9%) and grade III (55.7%). Fifty-four percent of the cases were triple negative. Invasive ductal carcinoma no special type was the commonest histotype (87.1%). Thirty-six percent (36%) of the cases expressed p53. Significant associations were found between p53 overexpression and histological grade (p = 0.034), triple negative (p = 0.0333) and luminal B (p<0.01) tumors. Most cases (93.1%) were negative for MDM2 expression. Significant association was found between MDM2 and HER2 over-expression as well as Ki-67. There was no significant positive correlation between MDM2 and p53 co-expression (p>0.05).ConclusionThe elevated level of p53 expression in the aggressive breast cancer phenotypes (high histological grade and triple negative) in our cohort suggest that P53 elevation may be a poor prognostic marker in our setting. High expression of MDM2 in our cohort with high Ki67; also in cases with Her2/neu overexpression known with predictable poor prognosis in the absence of target therapy suggest MDM2 may be associated with aggressive biological behaviour in our breast cancer cases. The non-significant association of p53 and MDM2 expression in the same cases as also documented by previous studies suggest independent genetic pathway in tumourigenesis.

6q deletion is frequent but unrelated to patient prognosis in breast cancer

BackgroundDeletions involving the long arm of chromosome 6 have been reported to occur in breast cancer, but little is known about the clinical relevance of this alteration.MethodsWe made use of a pre-existing tissue microarray with 2197 breast cancers and employed a 6q15/centromere 6 dual-labeling probe for fluorescence in situ (FISH) analysisResultsHeterozygous 6q15 deletions were found in 202 (18%) of 1099 interpretable cancers, including 19% of 804 cancers of no special type (NST), 3% of 29 lobular cancers, 7% of 41 cribriform cancers, and 28% of 18 cancers with papillary features. Homozygous deletions were not detected. In the largest subset of NST tumors, 6q15 deletions were significantly linked to advanced tumor stage and high grade (p < 0.0001 each). 6q deletions were also associated with estrogen receptor negativity (p = 0.0182), high Ki67 proliferation index (p < 0.0001), amplifications of HER2 (p = 0.0159), CCND1 (p = 0.0069), and cMYC (p = 0.0411), as well as deletions of PTEN (p = 0.0003), 8p21 (p < 0.0001), and 9p21 (p = 0.0179). However, 6q15 deletion was unrelated to patient survival in all cancers, in NST cancers, or in subsets of cancers defined by the presence or absence of lymph-node metastases.ConclusionOur data demonstrate that 6q deletion is a frequent event in breast cancer that is statistically linked to unfavorable tumor phenotype and features of genomic instability. The absence of any prognostic impact argues against a clinical applicability of 6q15 deletion testing in breast cancer patients.

Diversity of Cardiologic Issues in a Contemporary Cohort of Women With Breast Cancer.

Background: Women with breast cancer (BC) represent a special population particularly exposed to cardiovascular disease (CVD) risk. However, cardiologic assessment in BC is mostly limited to detection of left ventricular dysfunction cardiotoxicity (LVD-CTX) due to anticancer treatments. Our aim was to comprehensively investigate CV profile and events in a contemporary BC cohort.Methods and Results: Records of BC patients referred for a Cardio-Oncologic evaluation before starting anticancer treatments, between 2016 and 2019, were retrospectively reviewed (n = 508). Information regarding prevalence and control of CV risk factors, and novel CVD diagnoses were extracted. Occurrence of LVD-CTX, CV events other than LVD-CTX and mortality was assessed. Mean age of study population was 64 ± 13 years; 287 patients were scheduled to receive anthracycline and 165 anti-HER2 therapy. Overall, 53% of BC women had ≥2 CV risk factors, and 67% had at least one of arterial hypertension, dyslipidaemia or diabetes mellitus not adequately controlled. Eighteen (4%) patients were diagnosed a previously unknown CVD. Over a mean follow-up of 2.5 ± 1 years, 3% of BC patients developed LVD-CTX, 2% suffered from other CV events and 11% died. CV risk factors were not associated with LVD-CTX, except for family history of CAD. On the contrary, patients with other CV events exhibited a worse CV profile. Those who died more commonly experienced CV events other than LVD-CTX (p = 0.02).Conclusions: BC women show a suboptimal CV risk profile and are at risk of CV events not limited to LVD-CTX. A baseline Cardio-Oncologic evaluation was instrumental to implement CV prevention and to optimize CV therapies.

Genomic risk prediction of coronary artery disease in women with breast cancer: a prospective cohort study

BackgroundAdvancements in cancer therapeutics have resulted in increases in cancer-related survival; however, there is a growing clinical dilemma. The current balancing of survival benefits and future cardiotoxic harms of oncotherapies has resulted in an increased burden of cardiovascular disease in breast cancer survivors. Risk stratification may help address this clinical dilemma. This study is the first to assess the association between a coronary artery disease-specific polygenic risk score and incident coronary artery events in female breast cancer survivors.MethodsWe utilized the Studies in Epidemiology and Research in Cancer Heredity prospective cohort involving 12,413 women with breast cancer with genotype information and without a baseline history of cardiovascular disease. Cause-specific hazard ratios for association of the polygenic risk score and incident coronary artery disease (CAD) were obtained using left-truncated Cox regression adjusting for age, genotype array, conventional risk factors such as smoking and body mass index, as well as other sociodemographic, lifestyle, and medical variables.ResultsOver a median follow-up of 10.3 years (IQR: 16.8) years, 750 incident fatal or non-fatal coronary artery events were recorded. A 1 standard deviation higher polygenic risk score was associated with an adjusted hazard ratio of 1.33 (95% CI 1.20, 1.47) for incident CAD.ConclusionsThis study provides evidence that a coronary artery disease-specific polygenic risk score can risk-stratify breast cancer survivors independently of other established cardiovascular risk factors.

Serum selenium, selenoprotein P and glutathione peroxidase 3 as predictors of mortality and recurrence following breast cancer diagnosis: A multicentre cohort study

The trace element selenium is of essential importance for the synthesis of a set of redox active proteins. We investigated three complementary serum selenium status biomarkers in relation to overall survival and recurrence following diagnosis of primary invasive breast cancer in a large prospective cohort study. The Sweden Cancerome Analysis Network – Breast Initiative (SCAN-B) is a prospective population-based study including multiple participating hospitals. Main analyses included 1996 patients with a new diagnosis of primary invasive breast cancer, with blood sampling at the time of diagnosis. In sera of the patients, total serum selenium, selenoprotein P (SELENOP), and glutathione peroxidase 3 (GPx3) activity was analysed. All three biomarkers showed a positive correlation (p < 0.001), supporting the high quality of samples and analytical techniques. During a total of 13,306 person years of follow-up, 310 deaths and 167 recurrent breast cancer events occurred. In fully adjusted Cox models, all three biomarkers correlated inversely with mortality (p trend <0.001) and compared with the lowest quintile, hazard ratios (95% confidence interval) for overall survival in the highest quintile of selenium, SELENOP and GPx3 were 0.42 (0.28–0.63), 0.51 (0.36–0.73) and 0.52 (0.36–0.75), respectively. Low GPx3 activity was associated with more recurrences (Q5 vs Q1: fully adjusted HR (95%CI); 0.57 (0.35–0.92), (p trend = 0.005). Patients with low selenium status according to all three biomarkers (triple deficient) had the highest mortality risk with an overall survival probability of ∼50% after 8 years, in particular as compared to those having at least one marker in the highest quintile; fully adjusted HR (95%CI); 0.30 (0.21–0.43). Prediction of mortality based on all three biomarkers outperformed established tumour characteristics like histologic grade, number of involved lymph nodes or tumour size. An assessment of Se status at breast cancer diagnosis identifies patients at exceptionally high risk for a poor prognosis.

Single allele loss-of-function mutations select and sculpt conditional cooperative networks in breast cancer

The most common events in breast cancer (BC) involve chromosome arm losses and gains. Here we describe identification of 1089 gene-centric common insertion sites (gCIS) from transposon-based screens in 8 mouse models of BC. Some gCIS are driver-specific, others driver non-specific, and still others associated with tumor histology. Processes affected by driver-specific and histology-specific mutations include well-known cancer pathways. Driver non-specific gCIS target the Mediator complex, Ca++ signaling, Cyclin D turnover, RNA-metabolism among other processes. Most gCIS show single allele disruption and many map to genomic regions showing high-frequency hemizygous loss in human BC. Two gCIS, Nf1 and Trps1, show synthetic haploinsufficient tumor suppressor activity. Many gCIS act on the same pathway responsible for tumor initiation, thereby selecting and sculpting just enough and just right signaling. These data highlight ~1000 genes with predicted conditional haploinsufficient tumor suppressor function and the potential to promote chromosome arm loss in BC.

582Cost-effectiveness of AC-TH compared with TCH in new adjuvant therapy of breast cancer

Abstract Background To analyze the cost-effectiveness of Doxorubicin/cyclophosphamide/Paclitaxel/trastuzumab (AC-TH) and Docetaxel/Carboplatin/trastuzumab (TCH). Methods A Markov model was built to simulate the process of breast cancer events and death occurred in both AC-TH and TCH armed patients and to choose a suitable chemotherapy method. Data were collected from the clinical trials, some publicized literatures and patients’ diaries of a large Chinese comprehensive hospital. The cost-effectiveness analysis of two regimens and sensitivity analysis were performed using a Markov model. Results We identified 41 breast cancer patients at Hangzhou First People’s Hospital, among whom 15 (60%) had a partial response for AC-TH treatment and 13 (81.25%) had a partial response for TCH treatment. No cardiac toxicity was observed. Hematologic grade 3 or 4 toxicities were observed in 1 of 28 patients. Nonhematologic grade 3 or 4 toxicities with a reverse pattern were observed in 6 of 29 patients. The mean QALY gain per patient compared with TCH was 0.25 with ACTH, while the incremental costs were $US 13,142. The incremental cost-effectiveness ratio (ICER) of AC-TH versus TCH was $US 52,565 per QALY gained. Conclusions TCH neoadjuvant chemotherapy was feasible and active in HER2-overexpressing breast cancer patients in terms of the pathological complete response, complete response, and partial response rates and manageable toxicities. Key messages breast cancer; neoadjuvant chemotherapy; pharmaceutical economics; Markov model; cost-effectiveness analysis.

Abstract 1979: JAK2/STAT3 and TrkA pathways are frequently co-activated in triple-negative and HER2-enriched breast cancers and the co-activation correlates with an increased potential of metastasis

Abstract Breast cancer is the leading cause of cancer-related deaths in American women. Despite the current standard-of-care, which implements tumor resection, radiotherapy, and chemotherapy, triple-negative and HER2-positive breast cancer patients often relapse and present with recurrent disease, for which there is no cure. Thus, there is an urgent need to identify new molecular targets to improve patient response to anti-cancer therapies. The JAK2-STAT3 and TrkA receptor tyrosine kinase signaling pathways have been separately implicated in metastatic breast cancers, but information about their crosstalk remains limited. Activated Janus kinase 2 (JAK2) receptor tyrosine kinase phosphorylates signal transducer and activator of transcription 3 (STAT3) transcription factor, inducing STAT3 nuclear translocation and transcriptional activity. Abnormal activation of STAT3-mediated transcription has been identified as a pro-tumorigenic event in breast cancers and promotes progression through induction of breast cancer stem cells, invasion, and angiogenesis. Tropomyosin receptor kinase A (TrkA) frequently forms oncogenic fusion proteins and its overexpression has been shown to drive malignant transformation of breast cancer cells. JAK2 inhibitors, while approved for treatment of myeloproliferative neoplasms, are currently in clinical trials for triple-negative breast cancers. Currently, there are two FDA-approved TrkA inhibitors for treatment of NTRK1 fusion-positive solid tumors, one of which is considered a tumor-agnostic inhibitor. However, whether these two important pathways are co-activated in breast cancers and whether the co-activation is associated with overall progression of breast cancer have not been investigated. Herein, we report that STAT3 and TrkA are more co-activated in triple-negative and HER2-enriched breast cancers, compared to luminal subtypes, as determined by immunohistochemical staining of 33 invasive breast carcinomas and datamining data of over 1,500 breast cancer patients. We also observed that high co-activation of both JAK2-STAT3 and TrkA pathways significantly shortens overall metastasis-free survival of both triple-negative and HER2-enriched breast cancer patients when compared to patients with low co-activation. Similarly, we also find that JAK2-STAT3 and TrkA co-activation also significantly shortens brain, lung, and bone metastasis-free survival in both of these breast cancer subtypes, suggesting a critical role for JAK2-STAT3 and TrkA in distant metastasis of aggressive breast cancers. Taken together, our findings indicate a novel signaling crosstalk between JAK2-STAT3 and TrkA pathways in triple-negative and HER2-enriched breast cancers, and the use of their co-activation as a prognostic indicator for metastatic breast cancers of both subtypes. Citation Format: Angelina T. Regua, Noah R. Aguayo, Sara Abu Jalboush, Daniel L. Doheny, Sara G. Manore, Dongqin Zhu, Grace L. Wong, Austin Arrigo, Calvin J. Wagner, Yang Yu, Karen Baylon, Alexandra Thomas, Michael D. Chan, Jimmy Ruiz, Guangxu Jin, Roy E. Strowd, Peiqing Sun, Linda J. Metheny-Barlow, Jiayuh Lin, Hui-Wen Lo. JAK2/STAT3 and TrkA pathways are frequently co-activated in triple-negative and HER2-enriched breast cancers and the co-activation correlates with an increased potential of metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1979.

Patient-Derived Xenograft Engraftment and Breast Cancer Outcomes in a Prospective Neoadjuvant Study (BEAUTY).

Patient-derived xenografts (PDX) are a research tool for studying cancer biology and drug response phenotypes. While engraftment rates are higher for tumors with more aggressive characteristics, it is uncertain whether engraftment is prognostic for cancer recurrence. In a prospective study of patients with breast cancer treated with neoadjuvant chemotherapy (NAC) with taxane ± trastuzumab followed by anthracycline-based chemotherapy, we report the association between breast cancer events and PDX engraftment using tumors derived from treatment naïve (pre-NAC biopsies from 113 patients) and treatment resistant (post-NAC at surgery from 34 patients). Gray test was used to assess whether the cumulative incidence of a breast cancer event differs with respect to either pre-NAC PDX engraftment or post-NAC PDX engraftment. With a median follow-up of 5.7 years, the cumulative incidence of breast cancer relapse did not differ significantly according to pre-NAC PDX engraftment (5-year rate: 13.6% vs. 13.4%; P = 0.89). However, the incidence of a breast event was greater for patients with post-NAC PDX engraftment (5-year rate: 50.0% vs. 19.6%), but this did not achieve significance (P = 0.11). In treatment-naïve breast cancer receiving standard NAC, PDX engraftment was not prognostic for breast cancer recurrence. Further study is needed to establish whether PDX engraftment in the treatment-resistant setting is prognostic for cancer recurrence.

Radiation Without Endocrine Therapy in Older Women With Stage I Estrogen-Receptor-Positive Breast Cancer is Not Associated With a Higher Risk of Second Breast Cancer Events

The omission of radiation therapy (RT) in older women with stage 1 estrogen-receptor-positive (ER+) breast cancer receiving endocrine therapy (ET) is an acceptable strategy based on randomized trial data. Less is known about the omission of ET with or without RT. We analyzed surveillance, epidemiology, and end results (SEER)-Medicare data for 13,321 women age 66 years or older with stage I ER+ breast cancer from 2007 to 2012 who underwent breast-conserving surgery. Patients were classified into 4 groups: (1) ET+RT (reference); (2) ET alone; (3) RT alone; and (4) neither RT nor ET (NT). Second breast cancer events (SBCEs) were captured using the Chubak high-specificity algorithm. We used χ2 tests for descriptive statistics, multivariable multinomial logistic regression to estimate relative risk of undergoing a treatment, and multivariable, propensity-weighted competing-risks survival regression to estimate standardized hazard ratio (SHR) of SBCE. We set significance at P ≤ .01. Most women underwent both treatments, with 44% undergoing ET+RT, 41% RT alone, 6.6% ET alone, and 8.6% NT, but practice patterns varied over time. From 2007 to 2012, RT decreased from 49% to 30%, whereas ET alone and ET+RT increased (ET alone, 5.4%-9.6%; ET+RT, 38%-51%). Compared with patients age 66 to 69 years, patients age 80 to 85 years were more likely to receive NT (odds ratio [OR], 8.9), RT (OR, 1.9), or ET (OR, 8.8) versus ET+RT (P < .01). Three percent of subjects had an SBCE (2.2% ET+RT, 3.0% RT alone, 3.2% ET alone, 7.0% NT). Relative to ET+RT, NT and ET alone were associated with higher SBCE (NT: SHR, 3.7, P < .001; ET alone: SHR, 2.2, P=.008), whereas RT was not associated with a higher SBCE (SHR 1.21; P=.137). Clinical factors associated with higher SBCE were HER2 positivity and pT1c (SHR, 1.7; P=.006). Treatment with RT alone in older women with stage I ER+ disease is decreasing. RT alone is not associated with an increased risk for SBCE. By contrast, NT and ET are both associated with higher SBCE in multivariable analysis with propensity weighting. Further study of the omission of endocrine therapy in this patient population is warranted.

Do GLP-1 Receptor Agonists Increase the Risk of Breast Cancer? A Systematic Review and Meta-Analysis

Background: Risk of cancer is a major concern in the development of drugs for the treatment of obesity and diabetes. In randomized controlled trials (RCTs) of the liraglutide development program, a glucagon-like peptide-1 receptor agonist (GLP-1RA), subjects treated with the active drug had a higher absolute number of breast cancer events. Aim: To assess whether patients treated with GLP-1RAs had a higher risk of breast neoplasms. Methods: We searched MEDLINE, Embase, Web of Science, and CENTRAL from inception to February 8, 2020. Three pairs of reviewers examined and retrieved abstractsand full-text articles for RCTs of GLP-1RAs versus non-GLP-1RA controls(active or placebo) in adults with overweight, obesity, prediabetes, or diabetes,with a minimum follow-up period of 24 weeks and which reported at least oneevent of breast cancer or benign breast neoplasm. Divergences were dealt withby consensus. Researchers extracted study-level data and assessed within-study risk of bias with the RoB 2.0 tool and quality of evidence with GRADE. This study follows PRISMA reporting guidelines. Results: We included 52 trials, of which 50 reported breast cancer events and 11 reported benign breast neoplasms. Overall methodological quality was high. Among 48267 subjects treated with GLP-1RAs, 130 developed breast cancer compared to 107 of 40755 controls (relative risk [RR], 0.98; 95% confidence interval [CI], 0.76 to 1.26). Subset analyses according to follow-up, participant/investigator blinding, and type of GLP-1RA did not reveal any differences. The risk of benign breast neoplasms also did not differ between groups (RR, 0.99; 95% CI, 0.48 to 2.01). Trial sequential analysis provided evidence that the sample size was sufficient to avoid missing alternative results. Conclusion: Treatment with GLP-1RAs for obesity and diabetes does not increase the risk of breast neoplasms. Register: This systematic review was preregistered in PROSPERO (CRD42019132704).

AKT Inhibitors: New Weapons in the Fight Against Breast Cancer?

The serine/threonine kinase AKT is a key component of the PI3K/AKT/mTOR signaling pathway as it exerts a pivotal role in cell growth, proliferation, survival, and metabolism. Deregulation of this pathway is a common event in breast cancer including hormone receptor-positive (HR+) disease, HER2-amplified, and triple negative tumors. Hence, targeting AKT represents an attractive treatment option for many breast cancer subtypes, especially those resistant to conventional treatments. Several AKT inhibitors have been recently developed and two ATP-competitive compounds, capivasertib and ipatasertib, have been extensively tested in phase I and II clinical trials either alone, with chemotherapy, or with hormonal agents. Additionally, phase III trials of capivasertib and ipatasertib are already under way in HR+ and triple-negative breast cancer. While the identification of predictive biomarkers of response and resistance to AKT inhibition represents an unmet need, new combination strategies are under investigation aiming to boost the therapeutic efficacy of these drugs. As such, trials combining capivasertib and ipatasertib with CDK4/6 inhibitors, immune checkpoint inhibitors, and PARP inhibitors are currently ongoing. This review summarizes the available evidence on AKT inhibition in breast cancer, reporting both efficacy and toxicity data from clinical trials along with the available translational correlates and then focusing on the potential use of these drugs in new combination strategies.

Polymorphisms of T- cell leukemia 1A gene loci are not related to the development of adjuvant letrozole-induced adverse events in breast cancer

Letrozole, an aromatase inhibitor (AI), is the first-line adjuvant drug for treating hormone receptor-positive (HR+) breast cancer in postmenopausal women. However, harmful adverse events (AEs) and significant differences in drug response among individuals remain a significant problem in clinical application. Current evidence suggests that the observed individual variation in the treatment outcomes of AI is conferred by genetic variants. Hence, in this study, we examined the association of TCL1A gene polymorphisms with letrozole-induced AEs. The study subjects were postmenopausal HR+ breast cancer patients who were receiving adjuvant letrozole. Genomic DNA was isolated by a routine standard phenol-chloroform method. In total, 198 South Indian patients were genotyped for four single nucleotide polymorphisms (SNPs) in the TCL1A gene loci by the TaqMan allelic discrimination assay using the RT-PCR system. We used the odds ratio and 95% confidence interval to assess the genetic association. Musculoskeletal (MS) AEs and vasomotor symptoms (VMSs) are the most common side effects observed in the study cohort. Among 198 patients, 81 experienced musculoskeletal toxicity, reporting MS-AEs, 57 had VMSs, and 33 of them had both. The most frequently identified polymorphic variants in the patient series were rs11849538 (G), with an allele frequency of about 27.3%, followed by rs7158782-G (27.3%), rs7159713-G (25.8%), and rs2369049-G (22.5%). The genetic association analysis indicated no significant difference in the proportion of TCL1A gene variants between patients with and without AEs on either MS-AEs or VMSs. Though we observed high LD in all patient groups, the inferred haplotypes displayed a non-significant association with letrozole-induced specific AEs. However, the SNP functionality analysis by RegulomeDB provided a 2b rank score for rs7158782, suggesting a potential biological function. Our findings suggest that TCL1A gene polymorphisms may not play any role in the prediction of letrozole-induced AEs in South Indian HR+ breast cancer patients.

Molecular features of untreated breast cancer and initial metastatic event inform clinical decision-making and predict outcome: long-term results of ESOPE, a single-arm prospective multicenter study

BackgroundPrognosis evaluation of advanced breast cancer and therapeutic strategy are mostly based on clinical features of advanced disease and molecular profiling of the primary tumor. Very few studies have evaluated the impact of metastatic subtyping during the initial metastatic event in a prospective study. The genomic landscape of metastatic breast cancer has mostly been described in very advanced, pretreated disease, limiting the findings transferability to clinical use.MethodsWe developed a multicenter, single-arm, prospective clinical trial in order to address these issues. Between November 2010 and September 2013, 123 eligible patients were included. Patients at the first, untreated metastatic event were eligible. All matched primary tumors and metastatic samples were centrally reviewed for pathological typing. Targeted and whole-exome sequencing was applied to matched pairs of frozen tissue. A multivariate overall survival analysis was performed (median follow-up 64 months).ResultsPer central review in 84 patients (out of 130), we show that luminal A breast tumors are more prone to subtype switching. By combining targeted sequencing of a 91 gene panel (n = 67) and whole-exome sequencing (n = 30), a slight excess of mutations is observed in the metastases. Luminal A breast cancer has the most heterogeneous mutational profile and the highest number of mutational signatures, when comparing primary tumor and the matched metastatic tissue. Tumors with a subtype change have more mutations that are private. The metastasis-specific mutation load is significantly higher in late than in de novo metastases. The most frequently mutated genes were TP53 and PIK3CA. The most frequent metastasis-specific druggable genes were PIK3CA, PTEN, KDR, ALK, CDKN2A, NOTCH4, POLE, SETD2, SF3B1, and TSC2. Long-term outcome is driven by a combination of tumor load and metastasis biology.ConclusionsProfiling of the first, untreated, metastatic event of breast cancer reveals a profound heterogeneity mostly in luminal A tumors and in late metastases. Based on this profiling, we can derive information relevant to prognosis and therapeutic intervention, which support current guidelines recommending a biopsy at the first metastatic relapse.Trial registrationThe trial was registered at ClinicalTrials.gov (NCT01956552).

Explaining decisions of graph convolutional neural networks: patient-specific molecular subnetworks responsible for metastasis prediction in breast cancer

BackgroundContemporary deep learning approaches show cutting-edge performance in a variety of complex prediction tasks. Nonetheless, the application of deep learning in healthcare remains limited since deep learning methods are often considered as non-interpretable black-box models. However, the machine learning community made recent elaborations on interpretability methods explaining data point-specific decisions of deep learning techniques. We believe that such explanations can assist the need in personalized precision medicine decisions via explaining patient-specific predictions.MethodsLayer-wise Relevance Propagation (LRP) is a technique to explain decisions of deep learning methods. It is widely used to interpret Convolutional Neural Networks (CNNs) applied on image data. Recently, CNNs started to extend towards non-Euclidean domains like graphs. Molecular networks are commonly represented as graphs detailing interactions between molecules. Gene expression data can be assigned to the vertices of these graphs. In other words, gene expression data can be structured by utilizing molecular network information as prior knowledge. Graph-CNNs can be applied to structured gene expression data, for example, to predict metastatic events in breast cancer. Therefore, there is a need for explanations showing which part of a molecular network is relevant for predicting an event, e.g., distant metastasis in cancer, for each individual patient.ResultsWe extended the procedure of LRP to make it available for Graph-CNN and tested its applicability on a large breast cancer dataset. We present Graph Layer-wise Relevance Propagation (GLRP) as a new method to explain the decisions made by Graph-CNNs. We demonstrate a sanity check of the developed GLRP on a hand-written digits dataset and then apply the method on gene expression data. We show that GLRP provides patient-specific molecular subnetworks that largely agree with clinical knowledge and identify common as well as novel, and potentially druggable, drivers of tumor progression.ConclusionsThe developed method could be potentially highly useful on interpreting classification results in the context of different omics data and prior knowledge molecular networks on the individual patient level, as for example in precision medicine approaches or a molecular tumor board.

Risk of Breast Cancer in Selected Women With Atypical Ductal Hyperplasia Who do not Undergo Surgical Excision.

To review breast cancer incidence in women with ADH diagnosed by CNB and managed nonoperatively. ADH found on CNB is associated with an upgrade to carcinoma in 10%-50% of women, thus surgical excision remains the standard of care. Safety of nonoperative management is unknown. ADH patients diagnosed between January 2004 and October 2018 were identified. Subsequent breast cancer events were compared between those who were excised and those who met predetermined criteria of low risk and were thus observed. Subsequent breast cancer events were classified as index site event if identified in the same quadrant as prior ADH. Multivariable logistic regression models were used to assess potential predictors of subsequent breast cancer events. Four hundred seventy-eight women with 483 ADH lesions were identified; 309 were observed and 174 underwent excision. Median follow-up was 5.2 years. Prior breast cancer history was the only factor associated with subsequent breast cancer risk (odds ratio 2.25, 95% confidence interval 1.04-4.87). After excluding patients with a breast cancer history, there was no association of age, race, chemoprevention, or surgical excision of ADH with future cancer risk. 21/387 patients without a breast cancer history developed a subsequent cancer; 10 (7.3%) in the surgical group and 11 (4.4%) in the observed ( P = 0.2). Two cancers were identified at the index site in the surgery group (2/137, 1.5%) and three in those observed (3/250, 1.2%). Observation, rather than surgical excision, is safe in select women with ADH. National guidelines should consider observation for this select group of patients.

The impact of body mass index on breast cancer incidence among women at increased risk: an observational study from the International Breast Intervention Studies

BackgroundWe investigated the association between body mass index (BMI) and breast cancer risk in women at increased risk of breast cancer receiving tamoxifen or anastrozole compared with placebo using data from the International Breast Cancer Intervention Studies [IBIS-I (tamoxifen) and IBIS-II (anastrozole)].MethodsBaseline BMI was calculated from nurse assessed height and weight measurements for premenopausal (n = 3138) and postmenopausal (n = 3731) women in IBIS-I and postmenopausal women in IBIS-II (n = 3787). The primary endpoint was any breast cancer event (invasive and ductal carcinoma in situ). We used Cox proportional hazards regression to calculate hazard ratios (HRs) for risk after adjustment for covariates.ResultsThere were 582 (IBIS-I) and 248 (IBIS-II) breast cancer events [median follow-up = 16.2 years (IQR 14.4–17.7) and 10.9 years (IQR 8.8–13.0), respectively]. In adjusted analysis, women with a higher BMI had an increased breast cancer risk in both IBIS-I [HR = 1.06 per 5 kg/m2 (0.99–1.15), p = 0.114] and in IBIS-II [HR per 5 kg/m2 = 1.21 (1.09–1.35), p < 0.001]. In IBIS-I, the association between BMI and breast cancer risk was positive in postmenopausal women [adjusted HR per 5 kg/m2 = 1.14 (1.03–1.26), p = 0.01] but not premenopausal women [adjusted HR per 5 kg/m2 = 0.97 (0.86–1.09), p = 0.628]. There was no interaction between BMI and treatment group for breast cancer risk in either IBIS-I (p = 0.62) or IBIS-II (p = 0.55).ConclusionsHigher BMI is associated with greater breast cancer risk in postmenopausal women at increased risk of the disease, but no effect was observed in premenopausal women. The lack of interaction between BMI and treatment group on breast cancer risk suggests women are likely to experience benefit from preventive therapy regardless of their BMI.Trial registration Both trials were registered [IBIS-I: ISRCTN91879928 on 24/02/2006, retrospectively registered (http://www.isrctn.com/ISRCTN91879928); IBIS-II: ISRCTN31488319 on 07/01/2005, retrospectively registered (http://www.isrctn.com/ISRCTN31488319)]

Background Parenchymal Uptake on Molecular Breast Imaging and Breast Cancer Risk: A Cohort Study.

BACKGROUND. Background parenchymal uptake (BPU) on molecular breast imaging (MBI) was identified in a case-control study as a breast cancer risk factor beyond mammographic density. To our knowledge, this finding has not yet been confirmed in a cohort study. OBJECTIVE. The objectives of this study were to examine the association of BPU with breast cancer and to estimate the absolute risk and discriminatory accuracy of BPU in a cohort study. METHODS. A retrospective cohort was established that included women without a history of breast cancer who underwent MBI from 2004 to 2015. Radiologists who were blinded to future breast cancer diagnoses assessed BPU on baseline MBI examinations as low (photopenic or minimal) or elevated (mild, moderate, or marked). Associations of BPU with breast cancer were estimated using multivariable Cox proportional hazards models of the time to diagnosis. The 5-year absolute risk was calculated for study subgroups. The discriminatory accuracy of BPU was also assessed. RESULTS. Among 2992 women (mean age, 56.3 years; SD, 10.6 years) who underwent MBI, breast cancer events occurred in 144 women (median follow-up, 7.3 years). Median time to diagnosis after MBI was 4.2 years (range, 0.5-11.6 years). Elevated BPU was associated with a greater breast cancer risk (hazard ratio [HR], 2.39; 95% CI, 1.68-3.41; p ≤ .001). This association remained in postmenopausal women (HR, 3.50; 95% CI, 2.31-5.31; p < .001) but was not significant in premenopausal women (HR, 1.29; 95% CI, 0.72-2.32; p = .39). The 5-year absolute risk of breast cancer was 4.3% (95% CI, 2.9-5.7%) for women with elevated BPU versus 2.5% (95% CI, 1.8-3.1%) for those with low BPU. Postmenopausal women with dense breasts and elevated BPU had a 5-year absolute risk of 8.1% (95% CI, 4.3-11.8%) versus 2.8% (1.8-3.8%) for those with low BPU. Among postmenopausal women, discriminatory accuracy for invasive cancer was improved with the addition of BPU versus use of the Gail risk score alone (C statistic, 65.1 vs 59.1; p = .04) or use of the Breast Cancer Surveillance Consortium risk score alone (C statistic, 66.4 vs 60.4; p = .04). CONCLUSION. BPU on MBI is an independent risk factor for breast cancer, with the strongest association observed among postmenopausal women with dense breasts. In postmenopausal women, BPU provides incremental discrimination in predicting breast cancer when combined with either the Gail model or the Breast Cancer Surveillance Consortium model. CLINICAL IMPACT. Observation of elevated BPU on MBI may identify a subset of women with dense breasts who would benefit most from supplemental screening or preventive options.

Targeting PVT1 Exon 9 Re-Expresses Claudin 4 Protein and Inhibits Migration by Claudin-Low Triple Negative Breast Cancer Cells.

Simple SummaryTriple negative breast cancer accounts for 10–15% of all breast cancers. Specific molecular characteristics have led to the identification of six subtypes of triple negative breast cancer, with one in particular being claudin-low. PVT1, a non-protein coding gene, has been demonstrated to play an oncogenic role in various cancers. Specifically, PVT1 exon 9 has been shown to have oncogenic capability. In this study, we aimed to assess the role of PVT1 exon 9 in triple negative breast cancer cells. We have observed that siRNA targeting of PVT1 exon 9 in claudin-low triple negative breast cancer cells resulted in re-expression of claudin 4 protein, and inhibition of migration. These findings indicate that PVT1 exon 9 regulates claudin 4 expression and migration in triple negative breast cancer cells.PVT1 is a long non-coding RNA transcribed from a gene located at the 8q24 chromosomal region that has been implicated in multiple cancers including breast cancer (BC). Amplification of the 8q24 chromosomal region is a common event in BC and is associated with poor clinical outcomes. Claudin–low (CL) triple negative breast cancer (TNBC) is a subtype of BC with a particularly dismal outcome. We assessed PVT1 exon 9 expression in the T47D estrogen receptor positive BC cell line, and in the MDA MB 468 and MDA MB 231 TNBC cell lines, followed by the assessment of the expression of claudins 1, 3, 4 and 7, in MDA MB 468 and MDA MB 231 (TNBC) cells. We found that MDA MB 231 TNBC cells significantly express less claudin 1, 3, 4, and 7 than MDA MB 468 TNBC cells. PVT1 exon 9 is significantly upregulated in MDA MB 231 CL TNBC cells, and significantly downregulated in MDA MB 468 claudin high (CH) TNBC cells, in comparison to T47D estrogen receptor positive BC cells. We then analyzed the functional consequences of siRNA targeting of PVT1 exon 9 expression in the MDA MB 231 CL TNBC cells. Notably, siRNA targeting of PVT1 exon 9 expression in the MDA MB 231 CL TNBC cells led to a significant reduction in migration and the re-expression of claudin 4. Taken together, our data indicate that PVT1 exon 9 regulates claudin 4 expression and migration in CL TNBC cells, and may have clinical implications in CL TNBC.