Breast Cancer Patient Pathway Research Articles

Innovation in the management of the breast cancer patient pathway: from correct identification to target therapies. Perspectives, opportunities and insights

Innovation in the management of the breast cancer patient pathway: from correct identification to target therapies. Perspectives, opportunities and insights

Abstract PO5-13-10: Determining tumor-driving cell signaling pathways in breast cancer: Support for targeted therapy selection

Abstract Introduction: Success of therapeutic interventions largely rely on the pathological and biological characteristics of the tumor and varies due to the heterogeneous nature of breast cancers. Signal transduction pathways play an important role and are often used as target for specific therapies like hormone treatment, PI3K inhibitors etc. Immunohistochemistry (IHC) is currently the first assessment to divide tumors for subtyping and treatment and, especially in more advanced disease, mutation analyses are often used. Both IHC and mutation analyses only analyze a specific part of a signal transduction pathway and do not correlate well with outcome. Therefore, there is a need for new approaches to look at signaling pathways in cancer. We have developed a methodology that measures and quantifies signal transduction pathways (STPs) activities to reveal potential tumor-driving STPs to identify new options for targeted therapy in breast cancer. Method: Using the mRNA-based OncoSIGNal pathway activity profiling qPCR test (InnoSIGN), STP activities of 7 pathways (AR, ER, PI3K, MAPK, HH, TGFβ and Notch) were measured and quantified on a scale from 0-100. By using a set of non-tumor epithelial breast tissue samples, a reference range for normal physiological pathway activity was defined. A threshold was set on the 95th percentile of this range. A pathway activity score above this threshold was considered to be high (activated). Using this methodology, 201 ER positive (based on IHC) and 64 triple negative FFPE breast tumor samples obtained from different study sites and commercial biobanks were analyzed, including samples from primary and metastatic lesions, to determine for each individual tumor its pathway activity profile and identify activated tumor-driving pathways. Results: In the 195 primary ER positive tumors, the ER pathway was found to be activated in 78% of the samples, even though all samples were strongly ER immunohistochemistry stain positive. In addition to ER pathway activation, occasionally other pathways were activated: PI3K in 37%, HH in 25%, MAPK in 19%, AR in 20%, TGFβ in 6%, and Notch in 1%, of these samples. Analysis of 27 metastatic samples of ER positive tumors revealed in only 63% an active ER pathway. Additionally, more frequently PI3K pathway was observed in 70% of the samples. Other frequencies of pathway activation were: AR in 7% and MAPK in 4%, No Notch and TGFβ activity was found in this cohort. In 76 of the 78 triple negative tumors (TNBC) the ER pathway was inactive as expected. Remarkably, 2 samples appeared to have an activated ER pathway. An activated MAPK pathway was found in 50%, PI3K in 49%, HH in 18%, AR in 14%, TGFβ in 5% and Notch in 3% of these TNBC tumors. Conclusion: Compared to ER positive primary tumors we observed in metastatic ER positive tumors less frequent activation of the ER and more frequent activation of the PI3K pathway, suggesting that the latter pathway is associated with a more aggressive tumor phenotype. The triple negative subtype is characterized predominantly by activation of the PI3K, MAPK, AR and/or HH pathways, which may create new options for personalized targeted therapy of this subtype. OncoSIGNal can be used to determine the tumor driving signaling pathways in breast cancer patients, guiding selection of personalized targeted therapies. Citation Format: Paul van de Wiel, Yvonne Wesseling-Rozendaal, Anke Pierik, Dianne van Strijp, Saskia Vermeer, Fatema Tashrifwala, Josette Hartnett, Robert Babkowski, Suzanne Rose. Determining tumor-driving cell signaling pathways in breast cancer: Support for targeted therapy selection [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-13-10.

Type I interferons, inflammation, and fatigue in a longitudinal RNA study of women with breast cancer

BackgroundFatigue is a common side effect of cancer and its treatment and is thought to be driven in part by activation of the proinflammatory cytokine network. However, the cellular and molecular underpinnings of cancer-related fatigue (CRF) have not been determined, nor have immune pathways beyond inflammation been carefully investigated. The goal of this study was to examine the association between CRF and activation of canonical proinflammatory gene regulation pathways and Type I interferon (IFN) signaling pathways in breast cancer patients during and after treatment. MethodsWomen diagnosed with early-stage breast cancer (n = 181) completed assessments before and after treatment with radiation and/or chemotherapy and at 6, 12, and 18-month post-treatment follow-ups. Assessments included self-reported fatigue (Multidimensional Fatigue Symptom Inventory – Short Form) and expression of pre-specified sets of Type I IFN and pro-inflammatory immune response genes determined from mRNA sequencing of PBMCs. Mixed effect linear models examined changes in fatigue and immune gene expression over time and tested the hypothesis that fatigue would be associated with increased expression of Type I IFN and inflammatory response genes. ResultsThere were significant changes in fatigue and immune gene expression across the assessment period; all measures increased from pre- to post-treatment but showed diverging patterns over the follow-up, with declines in fatigue and persistent elevations in Type I IFN and proinflammatory gene expression. In mixed effect linear models, expression of Type I IFN response genes was elevated in association with fatigue across the assessment period, from pre-treatment to 18-month follow-up. In contrast, pro-inflammatory gene expression was associated with fatigue only at 6, 12, and 18-month follow-ups. Analyses controlling for changes in leukocyte subsets continued to show a significant association between fatigue and Type I IFN gene expression but reduced the time-dependent association with pro-inflammatory gene expression to non-significant. ConclusionsResults revealed unexpected complexity in the immune underpinnings of CRF and identify a novel role for IFN signaling as a robust contributor to this symptom before, during, and after treatment. Pro-inflammatory gene expression emerged as a predictor of fatigue later in the cancer trajectory, and that effect was primarily accounted for by a concurrent increase in monocyte prevalence.

Correction: Downgrading of referrals to breast cancer patient pathway

Correction: Downgrading of referrals to breast cancer patient pathway

Downgrading of referrals to breast cancer patient pathway.

The purpose of the study was to investigate whether the downgrading of external referrals to breast cancer patient pathways was clinically justifiable and led to a more correct prioritisation of patients who are referred to the specialist health service. The study included 214 external referrals to breast cancer patient pathways at the Breast Screening Centre, Oslo University Hospital, which were downgraded in 2020 since they did not meet the national criteria. The information obtained from electronic patient records included age, district of Oslo, name of referring doctor, outcome after investigation and treatment, as well as recommended timeframe for initiating the investigation. The quality of the referrals was also assessed. A total of 3% (7/214) of patients were diagnosed with breast cancer. Five were in the age group 40-50 years (9%, 5/56), one was over the age of 50 years (1/31) and one was in the age group 35-40 years (1/38). None were below the age of 35 years. A total of 95 doctors had their referrals downgraded. The study indicated that the downgrading of referrals to breast cancer patient pathways led to a more correct prioritisation of patients who are referred to the specialist health service. The results indicated that the downgrading was clinically justifiable for the age groups under 35 years and over 50 years, but that caution must be exercised when downgrading referrals in the age group 40-50 years.

Abstract P5-11-04: Differentially expressed genes and their pathways in breast cancer patients with mesenchymal CTC

Abstract Background: Circulating tumor cells (CTC) with phenotype of epithelial-mesenchymal transition (CTC_EMT) represent novel subpopulation of CTC associated with inferior outcome in primary breast cancer (PBC). However, molecular characterization of primary tumors associated with this CTC subpopulation is lacking. The aim of this study was to identify signaling pathways associated with presence of CTC_EMT in PBC patients using a comprehensive genomics approach. Methods: This translational study included 17 patients with PBC and 5 donors of normal breast tissue. CTC_EMT were detected before surgery by quantitative RT-PCR assay for expression of epithelial-mesenchymal transition (EMT) genes (TWIST1, SNAIL1, SLUG, ZEB1). Total RNA was extracted, in parallel, from fresh frozen primary tumor and whole-trancriptome profiles were obtained using RNA sequencing and additionally mRNAs profiles by microarray. Genes expressions were further validated by qRT-PCR. Results: Analyzing RNA sequencing and microarray data, we found set of genes differentially expressed in absence or presence of CTC_EMT in PBC. We identified 157 genes differentially expressed in CTC_EMT phenotype compared to patients with non-detectable CTC. Namely, keratin family is represented by genes KRT5, KRT14, KRT17. Gene ontologies related to membrane structure or communication and immunology appears to be involved in CTC-related processes, pathways related to cell junction and various signaling pathways including PI3K and Ras-signaling appear to be significant in processes leading to CTC EMT presence. Conclusions: We suspect multiple genes of having a role in primary tumour processes leading to CTC EMT production in breast cancer patients. Data suggest, that PI3K & Ras-signalling and pathways related to cell junction are the key pathways for changes inside of primary tumour tissue between CTC EMT and CTC- phenotype of breast cancer patients. We propose, additional study with single-cell resolution is needed for better understanding of the processes. Citation Format: Michal Mego, Dominik Hadzega, Gabriel Minarik, Andrea Soltysova, Petra Nemcova, Katarina Kalavska, Marian Karaba, Juraj Benca, Tatiana Sedlackova, Daniel Pindak, Lubos Klucar. Differentially expressed genes and their pathways in breast cancer patients with mesenchymal CTC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-11-04.

Down-regulation of miRNA 451a promotes many oncogenic signaling pathways in breast cancer patients

Down-regulation of miRNA 451a promotes many oncogenic signaling pathways in breast cancer patients

Bird’s eye view analysis of in situ cholesterol metabolic pathways in breast cancer patients and its clinicopathological significance in their subtypes

Obesity has been known to increase the risks of breast cancer (BC) development and also to be associated with adverse clinical outcome of the patients. Abnormalities of cholesterol metabolism are not only related to obesity but also to biological or clinical behavior of BC patients. However, which metabolites or pathways of cholesterol metabolism could represent the characteristics of BC patients have remained virtually unknown. Therefore, in this study, we attempted to perform bird’s eye view or comprehensive analysis of in situ or intra-tumoral cholesterol metabolic pathways using the multimodal approaches in order to elucidate the possible significance of cholesterol metabolites and its metabolic enzymes including CYP27A1, CYP7A1, and CYP46A1. GC-MS study using BC specimens was first performed in 60 BCE patients to evaluate cholesterol metabolism from cholesterol through oxysterols in both BC and normal tissues. Results of those analyses above lead to evaluating immunoreactivity and mRNA expression of CYP27A1, CYP7A1 and CYP46A1 in 213 and 153 BCE cases, respectively. Results of comprehensive GC-MS analysis did reveal that three oxysterols, 27-HC, 7α-HC and 24-HC were all related to malignant phenotypes in BC. 27-HC abundance was significantly associated with higher tumor stage (P = 0.0475) of BC patients. Luminal B type BC patients harboring high CYP27A1, the enzyme responsible for production of 27-HC were significantly associated with worse disease-free survival than those with low CYP27A1 (P = 0.0463). 7α-HC tended to be more abundant in HER2 positive and TNBC subtypes and higher levels of 7α-HC were also significantly associated with higher Ki-67 labeling index (P = 0.0022) and histological grade (P = 0.0286). CYP7A1, the enzyme involved in production of 7α-HC, was significantly more abundant in TNBC than other subtypes (vs Luminal A; P = 0.0321, vs Luminal B; P = 0.0048, vs HER2; P = 0.0103). The levels of 24-HC in BC were lower than normal breast tissues regardless of its subtypes. CYP46A1, the enzyme involved in the production of 24-HC, was detected only in 33 (15.5%) out of 213 BCE cases examined in this study. Results of our bird’s eye view analysis of in situ or intra-tumoral cholesterol metabolism in BC patients did firstly reveal BC subtype dependent involvement of its different pathways. Results also indicated the therapeutic possibility of subtype dependent modification of cholesterol metabolizing pathways in BC patients.

Abstract P2-08-20: Risk of everolimus- and alpelisib-induced hyperglycemia in obese and non-obese breast cancer patients with or without pre-existing hyperglycemia

Abstract Purpose:. Breast cancer is a common malignancy among women. About one in eight women in the US will be diagnosed with breast cancer during their lifetime. One of the most commonly altered genetic pathways in breast cancer patients is the PI3K/AKT/mTOR pathway. Among patients treated with everolimus and alpelisib, hyperglycemia is a frequently encountered adverse event. The cause of hyperglycemia is believed to be the inhibition of PI3K/mTOR, which not only plays a role in oncogenesis but also regulates glucose transportation and glycogen synthesis. Inhibition of PI3K/mTOR activity from treatment results in decreased insulin secretion and hyperglycemia. Obesity is a risk factor for both breast cancer and hyperglycemia. Over 70% of breast cancer patients seen in our center are overweight or obese. Being obese alone increases a patient’s risk of developing insulin resistance and hyperglycemia. Little research has been done on whether obese breast cancer patients are at higher risk of treatment induced hyperglycemia. The purpose of this study was to test whether obesity and pre-existing hyperglycemia are risk factors that increase the patients’ chance to develop hyperglycemia while being treated with anti-PI3K/mTOR drugs. Methods:. A retrospective study was performed on 119 breast cancer patients at Avera Cancer Institute. Female patients who had been treated with everolimus and/or alpelisib were included. According to the CDC standard, patients with body mass index (BMI) greater than 25 kg/m2 were considered as obese. Grade 2 and above hyperglycemia was defined as fasting blood glucose level greater than 160 mg/dl per CTCAE. Baseline blood glucose levels prior anti-PI3K/mTOR treatment were considered high if greater than 140 mg/dl per the American Diabetes Association. Results:. Of the 119 patients, 78 were ER+/HER2-; 22 were triple negative; 12 were ER-/HER2+ and 7 were ER+/HER2+. The BMI ranged from 17.79 to 52.87 (94 obese patients). Patients were kept on everolimus/alpelisib from 14 days to 5 years (median = 6 month). After starting everolimus/alpelisib, 17 patients developed hyperglycemia Grade 2 or greater, 16 of whom were obese. Being obese increased the odds of developing hyperglycemia under anti-PI3K/mTOR treatment by 4.58, However, this increase was not significant (p=0.16). Hyperglycemia in most patients was controlled by diet and lifestyle changes. Four patients (all obese) needed either insulin, metformin, DPP-4 and/or SGLT2 inhibitors to control blood glucose levels. Three patients had type 2 diabetes prior to therapy. The fourth patient developed Grade 3 hyperglycemia (>250 mg/dl) nine month after starting everolimus and was put on insulin for two months, with blood glucose returning back to normal. Everolimus was continued for another three month without causing hyperglycemia in this patient. Our data suggests that baseline blood glucose levels play a significant role in developing high grade hyperglycemia under anti-PI3K/mTOR treatment. The odds of developing hyperglycemia increase by a factor of 5.38 in patients with high blood glucose prior treatment (p= 0.007). Conclusion:. Being obese does not alone present a significantly higher risk of developing high grade hyperglycemia while being treated with anti-PI3K/mTOR drugs compared to non-obese patients if their blood glucose is well controlled. Most patients can manage their blood glucose level by diet and lifestyle changes. Patients starting anti-PI3K/mTOR treatment with high blood glucose level at baseline are at a much higher risk of developing drug-induced hyperglycemia and should be closely monitored. Citation Format: Bing Xu, Tobias Messiner, Casey Williams. Risk of everolimus- and alpelisib-induced hyperglycemia in obese and non-obese breast cancer patients with or without pre-existing hyperglycemia [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 P2-08-20.

POSC97 Breast Cancer Patient Pathway: Direct Costs for the Portuguese NHS of a Breast Cancer Patient

Breast Cancer (BC) is the most prevalent cancer among Portuguese women, being responsible for significant socio-economic burden. Every year there are 7.500 new cases and over 1.700 women die from this disease. To estimate the direct costs for the NHS of a BC patient, a model was built based on the patient pathway.

Investigating the role of Wnt and related signaling pathways in breast cancer patients: Thesis Abstract

Thesis Abstract Background: Breast cancer is a heterogeneous malignant tumor that includes several types of cells. Among them, only breast cancer stem cells (BCSCs) have tumorigenic ability. In this study we tested the hypothesis that BCSCs are behind disparities in behavior and biology of breast cancer between different ethnic groups and it is very important to investigate signaling pathways regulating BCSCs in each population. Therefore, we investigated the role of WNT, HH and apoptosis signaling pathways together with ALDH1A1 and CD44 in BCSCs resistance to chemotherapy in tumor biopsies collected from Egyptian patients compared to British patients. Aim: We investigated the expression levels of specific members of Wnt, Hedgehog, and apoptosis signaling pathways in BCSCs isolated from treated Egyptian and British patients. The change in their expression levels between the two populations was detected. Materials and Methods: Breast Cancer tumors were collected from Egyptian and British patients, dissociated to a single cell suspension in collagenase IV containing buffer. CSCs were isolated using anoikis resistance assay from treated and untreated samples. RNA was extracted and cDNA was synthesized. Custom qPCR arrays were used to detect the gene expression of Wnt5A, CXCR4, LEF1, TCF4, SHH, GLI1, BCL2, XIAP, ALDH1A1and CD44. Data were analyzed by ΔΔCt method. Results: Our data showed a number of genes with different expression levels in the treated Egyptian patients compared to the treated British patients. Conclusion: Molecular mechanisms that regulate BCSCs differ from a population to another. Moreover, the different treatment regimens in different countries may affect the way BCSCs resist therapy.

Investigating the role of Notch and related signaling pathways in Breast cancer patients: Thesis Abstract

Thesis Abstract Breast cancer is the most common cancer in women worldwide . Cancer Stem Cells play an important role in the processes of drug resistance and metastasis. Studies showed that behavior and biology of B.C differ in different racial groups, emphasizing the importance of understanding the biology of the disease in each population separately. Here we investigated the differential expression of a number of CSCs regulating genes in Egyptian and British patients. we have studied the influence of cancer therapy on the expression levels of these genes. Method:CSCs were isolated from a total of 24 B.C patients from Egypt and England, using Anoikis resistance assay. RNA was extracted, its concentration and quality were measured by nano drop, bioanalyzer and qPCR) and cDNA was then synthesized. qPCR arrays harboring primers specific for (Notch1,Notch4,Nanong, JAG1, PARP1, HIF1A, SP1, STAT1, NFKB1, DNMT1, DNMT3B) were designed. The differential gene expression between; Egyptian untreated vs British untreated, Egyptian treated vs British treated, Egyptian untreated vs Egyptian treated, and British untreated vs British treated was detected using ΔΔCt method. Results: We have detected which genes of the genes under study are differentially expressed between Egyptians and British patients. we determined which genes in both racial groups may be responsible for CSCs resistance to therapy. Conclusion: Our study strongly confirms the racial variation in B.C biology and is the first study to show that CSCs signaling pathways are behind this variation. More importantly, we detected which genes showed be targeted to sensitize CSCs to therapy in Egyptian patients.

Patient involvement in the development of the Danish surgical breast cancer patient pathway – An action research project

Although patient involvement is on the political agenda, the influence on clinical practice is poorly described. The aim of this study was to explore and evaluate the participatory process of involving patients and relatives in development of a surgical breast cancer patient pathway. The overall design was insider action research and included two Danish surgical breast cancer clinics. In dialogue meetings patients, relatives, and healthcare professionals (HCPs) discussed suggestions for improving the pathway. Patients and relatives were satisfied with the pathway organisation in general. However, suggestions related to information, communication, and choice of treatment were presented. In response to this, a patient decision aid was developed, tested, and implemented, and HCPs increased focus on male relatives, and made minor changes to the pathway. Participants were satisfied with the participatory process, however, recommendations for future dialogue meetings included shortening the follow-up period, using a skilled facilitator, reminding HCPs being open-minded, and emphasizing for patients and relatives that participation may require a surplus of mental resources. Overall, recommendations on patient involvement obtained from this project could, due to their general relevance, be implemented in clinical settings other than breast cancer. Furthermore, action research proved a suitable design for research on patient involvement.

Improving the breast cancer patient pathway using a consultant breast radiographer

Background: Adjuvant breast, nodal and chest wall radiotherapy comprises a significant workload of all radiotherapy centres. Improvement in cancer patients’ experience and reductions in waiting times are both factors at the forefront of NHS England’s drive to achieving world-class cancer treatment.1 Allied health professionals are increasingly being developed into specialty consultant roles to meet these targets.2 This skill mix is essential given the national consultant oncology work force challenge.3, 4

Surgical breast cancer patient pathway: Experiences of patients and relatives and their unmet needs.

Background and aimBreast cancer is the most common cancer disease in women worldwide. In Denmark, the law prescribes cancer patient pathways (CPPs) in general and thus also for breast cancer. Although results from patient satisfaction surveys show overall satisfaction with the pathway, a call for improvement has been voiced for some areas. The aim of this study was to explore patients’ and relatives’ experiences with the surgical breast CPP and to identify any unmet needs.MethodThis study was based on focus groups with patients who had surgery for breast cancer, and their relatives. The settings were two Danish surgical breast cancer clinics.FindingsOverall, patients and relatives found the structure of the surgical breast CPP satisfactory. The time in the surgical department was short, and most patients found it difficult to cope with the situation. Empathy and a supportive relationship between patients, relatives and health‐care professionals were of great importance. Five key points were identified in which some of the participants had unmet needs. Suggestions for change were related to information, communication, choice of treatment, flexibility in the pathway and easy access to the clinic after surgery.ConclusionAlthough patients and relatives found the CPP for breast cancer satisfactory and well planned, suggestions for change were made relating to unmet needs with respect to five key points in the pathway. Implementing findings from this study in clinical practice requires co‐operation between health‐care professionals and support from the leaders of the organization.

Optimise not compromise: The importance of a multidisciplinary breast cancer patient pathway in the era of oncoplastic and reconstructive surgery.

Modern breast cancer care is a complex multidisciplinary undertaking in which the integrated function of multiple constituent parts is critical, and where changes to one therapeutic component may profoundly influence the delivery and outcomes of another. Oncoplastic and reconstructive breast surgery has evolved in the era of longer survival rates for women with breast cancer and aims to enhance oncological and cosmetic outcomes. However, concurrently there has been an expansion in the indications for post-mastectomy radiation therapy (Abdulkarim et al., 2011; Early Breast Cancer Trialists' Collaborative Group (EBCTCG), 2014; Poortmans et al., 2015; Wang et al., 2011), the recognition of several biologically distinct breast cancer subtypes (Perou et al., 2000; Sørlie et al., 2001, 2003; Cheang et al., 2008, 2009; Sotiriou et al., 2003; Millar et al., 2011; Blows et al., 2010; Schnitt, 2010; Haque et al., 2012; Dai et al., 2015) and the development of recommendations for prophylactic surgery for high-risk women, including BRCA-mutation carriers (James et al., 2006; Domchek et al., 2010). Primary systemic therapy is increasingly utilised yet has varying efficacy depending on tumour biology (Cortazar et al., 2014). In this paper we review the evidence which informs the multidisciplinary team opinion in the era of oncoplastic and reconstructive breast surgery. We aim to describe an optimal multidisciplinary approach which balances competing risks of multimodal therapies to optimise oncological and cosmetic outcomes.

Why Do Women with Breast Cancer Get Diagnosed and Treated Late in Sub-Saharan Africa Perspectives from Women and Patients in Bamako, Mali

Background: Breast cancer, the most common cancer among women worldwide, has a high mortality rate in low-income countries. In sub-Saharan Africa, most breast cancer patients are diagnosed with advanced disease. Some studies have quantified the time delay to diagnosis in sub-Saharan Africa, but very few have used qualitative methods to understand barriers leading to delay. This study analyses barriers throughout a breast cancer patient's pathway from symptom recognition to treatment in Mali. Method: Three focus group discussions were conducted. The model of pathways to treatment was used to structure the results into 4 time intervals: appraisal, help-seeking, diagnosis, and treatment, with a focus on barriers during each interval. Results: The main barriers during the appraisal interval were a low level of breast cancer knowledge among women, their families, and medical professionals, and during the help-seeking interval, mistrust in the community health care centers and economic hardship. Barriers during the diagnosis interval were low quality of health care services and lack of social support, and during the pretreatment interval high costs and lack of specialized services. Conclusion: Multilevel interventions are needed to ensure access, availability, and affordability of a minimum standard of care for breast cancer patients in sub-Saharan Africa.

Stepwise analysis of MIR9 loci identifies miR-9-5p to be involved in Oestrogen regulated pathways in breast cancer patients

miR-9 was initially identified as an epigenetically regulated miRNA in tumours, but inconsistent findings have been reported so far. We analysed the expression of miR-9-5p, miR-9-3p, pri-miRs and MIR9 promoters methylation status in 131 breast cancer cases and 12 normal breast tissues (NBTs). The expression of both mature miRs was increased in tumours as compared to NBTs (P < 0.001) and negatively correlated with ER protein expression (P = 0.005 and P = 0.003, for miR-9-3p and miR-9-5p respectively). In addition, miR-9-5p showed a significant negative correlation with PgR (P = 0.002). Consistently, miR-9-5p and miR-9 3p were differentially expressed in the breast cancer subgroups identified by ER and PgR expression and HER2 amplification. No significant correlation between promoter methylation and pri-miRNAs expressions was found either in tumours or in NBTs. In the Luminal breast cancer subtype the expression of miR-9-5p was associated with a worse prognosis in both univariable and multivariable analyses. Ingenuity Pathway Analysis exploring the putative interactions among miR-9-5p/miR-9-3p, ER and PgR upstream and downstream regulators suggested a regulatory loop by which miR-9-5p but not miR-9-3p is induced by steroid hormone receptor and acts within hormone-receptor regulated pathways.

Heterozygous PALB2 c.1592delT mutation channels DNA double-strand break repair into error-prone pathways in breast cancer patients.

Hereditary heterozygous mutations in a variety of DNA double-strand break (DSB) repair genes have been associated with increased breast cancer risk. In the Finnish population, PALB2 (partner and localizer of BRCA2) represents a major susceptibility gene for female breast cancer, and so far, only one mutation has been described, c.1592delT, which leads to a sixfold increased disease risk. PALB2 is thought to participate in homologous recombination (HR). However, the effect of the Finnish founder mutation on DSB repair has not been investigated. In the current study, we used a panel of lymphoblastoid cell lines (LCLs) derived from seven heterozygous female PALB2 c.1592delT mutation carriers with variable health status and six wild-type matched controls. The results of our DSB repair analysis showed that the PALB2 mutation causes specific changes in pathway usage, namely increases in error-prone single-strand annealing (SSA) and microhomology-mediated end-joining (MMEJ) compared with wild-type LCLs. These data indicated haploinsufficiency regarding the suppression of error-prone DSB repair in PALB2 mutation carriers. To the contrary, neither reduced HR activities, nor impaired RAD51 filament assembly, nor sensitization to PARP inhibition were consistently observed. Expression of truncated mutant versus wild-type PALB2 verified a causal role of PALB2 c.1592delT in the shift to error-prone repair. Discrimination between healthy and malignancy-presenting PALB2 mutation carriers revealed a pathway shift particularly in the breast cancer patients, suggesting interaction of PALB2 c.1592delT with additional genomic lesions. Interestingly, the studied PALB2 mutation was associated with 53BP1 accumulation in the healthy mutation carriers but not the patients, and 53BP1 was limiting for error-prone MMEJ in patients but not in healthy carriers. Our study identified a rise in error-prone DSB repair as a potential threat to genomic integrity in heterozygous PALB2 mutation carriers. The used phenotypic marker system has the capacity to capture dysfunction caused by polygenic mechanisms and therefore offers new strategies of cancer risk prediction.

Breast cancer information and support needs for women with intellectual disabilities: a scoping study

To examine the compass and nature of relevant research and identify gaps in the current evidence in order to determine the priority of future research about breast cancer and intellectual disability (ID). A scoping study that comprised of a consultation exercise with a wide range of key stakeholders (n = 26) from one northern city (Sheffield) within the UK. This study identified numerous gaps in the current evidence base. It highlighted a dearth of research that focuses specifically on the information and support needs of women with IDs (and their carers) across the breast cancer patient pathway. Within the interviews, whilst 'reasonable adjustments' were being made and there was evidence of good practice, they were neither strategic nor systematic. Participants suggested that future research should focus on devising protocols to advise on the legal, ethical and clinical imperatives so that clinical governance in this area is assured. There remains a dearth of research or practice guidelines at every stage of the breast cancer care pathway for women with ID. This may arguably lead to late diagnosis, suboptimal treatment and management and overall survival rates for this group. Further research is needed to understand the specific information and support needs of both women with ID (and their formal and informal carers) through the breast care pathway and to identify appropriate protocols, strategies and interventions in order to address these.