Distinct Inflammatory Phenotypes are associated with subclinical and clinical Cardiovascular disease in People living with HIV.

Despite inflammation being implicated in cardiovascular disease (CVD) in people with HIV (PWH), considerable heterogeneity within populations of PWH exists. Stratifying CVD risk based on inflammatory phenotype could play an important role. Using principal component analyses and unsupervised hierarchical clustering, we examined 38 biomarkers to identify inflammatory phenotypes in two independent cohorts of PWH. We identified three distinct inflammatory clusters present in both cohorts that associated with altered risk of both subclinical CVD (cohort 1) and prevalent clinical CVD (cohort 2) after adjusting for CVD risk factors. These data support precision medicine approaches to enhance CVD risk assessment in PWH.

Quantifying the impact of regional variations in COVID-19 infections and hospitalizations across Ireland.

BACKGROUND: As most COVID-19 transmission occurs locally, targeted measures where the likelihood of infection and hospitalization is highest may be a prudent risk management strategy. To date, in the Republic of Ireland, a regional comparison of COVID-19 cases and hospitalizations has not been completed. Here, we investigate (i) the variation in rates of confirmed infection and hospital admissions within geographical units of the Republic of Ireland and (ii) frequency of deviations in risk of infection or risk of hospitalization. METHODS: We analyzed routinely collected, publicly available data available from the National Health Protection and Surveillance Centre and Health Service Executive from nine geographical units, known as Community Health Organization areas. The observational period included 206 14-day periods (1 September 2020-15 April 2021). RESULTS: A total of 206 844 laboratory-confirmed cases and 7721 hospitalizations were reported. The national incidence of confirmed infections was 4508 [95% confidence interval (CI) 4489-4528] per 100 000 people. The risk of hospital admission among confirmed cases was 3.7% (95% CI 3.5-3.9). Across geographical units, the likelihood that rolling 14-day risk of infection or hospitalization exceeded national levels was 9-86% and 0-88%, respectively. In the most affected regions, we estimate this resulted in an excess of 15 180 infections and 1920 hospitalizations. CONCLUSIONS: Responses to future COVID-19 outbreaks should consider the risk and harm of infection posed to people living in specific regions. Given the recent surges of COVID-19 cases in Europe, every effort should be made to strengthen local surveillance and to tailor community-centred measures to control transmission.

Antiretroviral treatment outcomes among late HIV presenters initiating treatment with integrase inhibitors or protease inhibitors.

OBJECTIVES: The aim of the study was to investigate the efficacy and safety of first-line antiretroviral therapy (ART) with integrase inhibitor (INI) or protease inhibitor (PI)-based regimens in patients with low CD4 cell counts and/or an AIDS-defining disease. METHODS: We conducted a retrospective, multicentre analysis to investigate discontinuation proportions and virological response in patients with CD4 cell counts < 200 cells/µL and/or AIDS-defining disease when starting first-line ART. Proportions of those discontinuing ART were compared using univariate analysis. Virological response was analysed using the Food & Drug Administration (FDA) snapshot analysis (HIV-1 RNA < 50 HIV-1 RNA copies/mL at week 48). RESULTS: Two hundred and eighteen late presenters were included in the study: 13.8% were women and 23.8% were of non-European ethnicity, and the mean baseline CD4 count was 91 cells/µL (standard deviation 112 cells/µL). A total of 131 late presenters started on INI- and 87 on PI-based treatment. It was found that 86.1% of patients treated with INIs and 81.1% of patients treated with PIs had a viral load < 50 copies/mL at week 48; proportions of discontinuation because of adverse events were 6.1% in the INI group and 11.5% in the PI group. No significant differences in discontinuation proportions were observed at week 12 or 48 between INI- and PI-based regimens (P = 0.76 and 0.52, respectively). Virological response was equally good in those receiving INIs and those receiving PIs (86.1% vs. 81.1%, respectively; P = 0.36). CONCLUSIONS: In a European cohort of late presenters starting first-line INI or PI-based ART regimens, there were no significant differences in discontinuation proportions or virological response at week 48.

Estimated glomerular filtration rate slopes on tenofovir alafenamide.

OBJECTIVES: The aim of the study was to analyse and compare estimated glomerular filtration rate (eGFR) slopes during exposure to tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) in individuals who initiated TAF, regardless of prior regimen, before October 2016. METHODS: An observational cohort study was conducted at 11 clinics in the UK and Ireland. Mixed effects models with random intercept and time terms fitted were used to generate and compare eGFR slopes while participants were exposed to TDF and TAF, with adjustment for age, eGFR at TDF/TAF initiation, gender, ethnicity, and time-updated CD4 cell count and HIV RNA measurements. RESULTS: Data were available for 357 subjects (median age 50 years; 80% male; 82% white/other ethnicity; 51% men who have sex with men; median nadir CD4 count 216 cells/µL). The median duration of exposure to TAF was 2.0 (interquartile range 1.6, 2.3) years. At TAF initiation, the median CD4 count was 557 cells/µL, the median eGFR was 80 mL/min/1.73 m2, and 86% had suppressed HIV infection. The mean adjusted eGFR slope during TDF and TAF exposure was -2.08 [95% confidence interval (CI) -2.24, -1.92] and 1.18 (95% CI 0.20, 1.52) mL/min/1.73 m2/year, respectively (P < 0.001). Individuals who experienced rapid eGFR decline (> 3 or 5 mL/min/1.73 m2/year) while receiving TDF experienced significant eGFR recovery while on TAF (P < 0.001). CONCLUSIONS: Significant improvement in eGFR slope was observed in patients who switched from TDF- to TAF-containing antiretroviral regimens. These data provide further support for the renal safety of TAF, and for switching those who experience progressive worsening of renal function from TDF to TAF.

Level of agreement between frequently used cardiovascular risk calculators in people living with HIV.

OBJECTIVES: The aim of the study was to describe agreement between the QRISK2, Framingham and Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cardiovascular disease (CVD) risk calculators in a large UK study of people living with HIV (PLWH). METHODS: PLWH enrolled in the Pharmacokinetic and Clinical Observations in People over Fifty (POPPY) study without a prior CVD event were included in this study. QRISK2, Framingham CVD and the full and reduced D:A:D CVD scores were calculated; participants were stratified into 'low' (< 10%), 'intermediate' (10-20%) and 'high' (> 20%) categories for each. Agreement between scores was assessed using weighted kappas and Bland-Altman plots. RESULTS: The 730 included participants were predominantly male (636; 87.1%) and of white ethnicity (645; 88.5%), with a median age of 53 [interquartile range (IQR) 49-59] years. The median calculated 10-year CVD risk was 11.9% (IQR 6.8-18.4%), 8.9% (IQR 4.6-15.0%), 8.5% (IQR 4.8-14.6%) and 6.9% (IQR 4.1-11.1%) when using the Framingham, QRISK2, and full and reduced D:A:D scores, respectively. Agreement between the different scores was generally moderate, with the highest level of agreement being between the Framingham and QRISK2 scores (weighted kappa = 0.65) but with most other kappa coefficients in the 0.50-0.60 range. CONCLUSIONS: Estimates of predicted 10-year CVD risk obtained with commonly used CVD risk prediction tools demonstrate, in general, only moderate agreement among PLWH in the UK. While further validation with clinical endpoints is required, our findings suggest that care should be taken when interpreting any score alone.

Two-drug vs. three-drug combinations for HIV-1: Do we have enough data to make the switch?

Three-drug combination antiretroviral therapy (ART) became available in 1996, dramatically improving the prognosis of people living with HIV. The clinical benefits of ART are due to the sustained viral load suppression and CD4 T cell gains. Major drawbacks of the first ART regimens were adverse events, and high pill burden, which led to the reduction of drug adherence resulting in frequent treatment discontinuations and the development of drug resistance. Due to increased viral potency of new antiretroviral drugs consideration of a two-drug combination therapy repositioning occurred in an effort to reduce adverse events, drug-drug interactions and cost, while maintaining a sustained antiviral effect. Various combinations of two-drug regimens have been studied, and non-inferiority compared to a three-drug regimen has been shown only for some of them. In addition, a two-drug combination regimen may not be suitable for every patient, especially those who are pregnant, those with tuberculosis or coexisting HBV infection. Furthermore no information has been generated concerning the secondary transmission of HIV from patients who have undetectable plasma viral load on two-drug regimens. Additional studies of two-drug combinations are also necessary to evaluate the debated existence of low viral replication in tissues and on immune activation. While there is no urgent need to routinely switch patients to two-drug combination therapy, due to the availability of drug combinations without significant toxicities, dual regimens represent a suitable option that deserve long-term evaluation before being introduced to clinical practice.

Week 96 results of the randomized, multicentre Maraviroc Switch (MARCH) study.

OBJECTIVES: The Maraviroc Switch (MARCH) study week 48 data demonstrated that maraviroc, a chemokine receptor-5 (CCR5) inhibitor, was a safe and effective switch for the ritonavir-boosted protease inhibitor (PI/r) component of a two nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] plus PI/r-based antiretroviral regimen in patients with R5-tropic virus. Here we report the durability of this finding. METHODS: MARCH, an international, multicentre, randomized, 96-week open-label switch study, enrolled HIV-1-infected adults with R5-tropic virus who were stable (> 24 weeks) and virologically suppressed [plasma viral load (pVL) < 50 HIV-1 RNA copies/mL]. Participants were randomized to continue their current PI/r-based regimen (PI/r) or to switch to MVC plus two N(t)RTIs (MVC) (1:2 randomization). The primary endpoint was the difference in the proportion with pVL < 200 copies/mL at 96 weeks. The switch arm was defined as noninferior if the lower limit of the 95% confidence interval (CI) for the difference was < -12% in the intention-to-treat (ITT) population. Safety endpoints (the difference in the mean change from baseline or a comparison of proportions) were analysed as key secondary endpoints. RESULTS: Eighty-two (PI/r) and 156 (MVC) participants were randomized and included in the ITT analysis; 71 (87%) and 130 (83%) were in follow-up and on therapy at week 96. At week 96, 89.0% and 90.4% in the PI/r and MVC arms, respectively, had pVL < 50 copies/mL (95% CI -6.6, 10.2). Moreover, in those switching away from PI/r, there were significant reductions in mean total cholesterol (differences 0.31 mmol/L; P = 0.02) and triglycerides (difference 0.44 mmol/L; P < 0.001). Changes in CD4 T-cell count, renal function, and serious and nonserious adverse events were similar in the two arms. CONCLUSIONS: MVC as a switch for a PI/r is safe and effective at maintaining virological suppression while having significant lipid benefits over 96 weeks.

The inframammary skin-sparing mastectomy technique.

Skin-sparing mastectomy and immediate implant-based breast reconstruction is technically a challenging procedures for women with large, ptotic breasts. This is usually performed using the Wise pattern incision resulting in an inverted T scar, which is associated with postoperative complications. The other challenge is obtaining adequate coverage of the prosthesis. We describe a technique that avoids the inverted T scar and provides a single horizontal scar with a double dermo-muscular layer coverage of the prosthesis.

The HIV Care Cascade and sub-analysis of those linked to but not retained in care: the experience from a tertiary HIV referral service in Dublin Ireland.

BACKGROUND: The HIV Care Cascade model can be used to measure how clinical services align with United Nations' (UN) HIV treatment targets. Previous models have highlighted sequential losses at each step of the Cascade with a significant proportion being not retained in care (NRIC). OBJECTIVE: We aimed to assess the feasibility of meeting the UN targets and assess factors associated with, and calculate the true proportion of those, NRIC. METHODS: All people living with HIV who were linked to our service, one of three specialist HIV care providers in Dublin Ireland, from its establishment in 1993 to 1 December 2014, were included in the cohort and were categorized as linked to care, retained in care (RIC), on antiretroviral therapy (on ART), virally suppressed (HIV RNA <40copies/ml), and NRIC. An analysis of those NRIC was performed to categorize their current status through direct/indirect contact. RESULTS: Of 1000 patients linked to care, 78.7% (n = 787) were RIC, of whom 91.5% (n = 720) were on ART, with 89.9% (n = 644) virally suppressed. Those RIC were more likely older (p = 0.006) and non-IVDU (p < 0.001). Of 213 (21.3%) NRIC, 56 (26.3%) emigrated, 27 (12.7%) transferred care, 15 (7.0%) stopped attending but were contactable, 38 (17.8%) died, and 77 (36.1%) were lost to follow-up. After revision, 10.5% of the cohort was confirmed as NRIC, with 6 of 15 defined as "stopped attending" re-linked to care following direct contact. CONCLUSIONS: Our HIV Care Cascade model demonstrates that the true numbers of patients NRIC may be significantly lower than previously estimated and once RIC, treatment goals approaching the United Nations Programme on HIV and AIDS targets are possible with 91.5% on treatment and almost 90% of those on treatment virally suppressed. That 40% reengaged following direct contact suggests benefit through regular monitoring and direct contact based on the HIV Care Cascade model.

Associations between cognitive impairment and patient-reported measures of physical/mental functioning in older people living with HIV.

OBJECTIVES: While cognitive impairment is frequently reported in HIV-positive individuals and has historically been associated with poorer functional outcomes, the associations between cognitive impairment and patient-reported outcome measures (PROMs) in contemporary cohorts are unclear. METHODS: We tested cognitive function using a computerized battery (CogState™ ) in 290 HIV-positive and 97 HIV-negative individuals aged ≥ 50 years participating in the Pharmacokinetic and Clinical Observations in People Over Fifty (POPPY) study. Participants completed questionnaires detailing physical and mental health [Short Form Health Survey (SF-36)], cognitive function [European AIDS Clinical Society (EACS) questions], activities of daily living [Lawton Instrumental Activities of Daily Living (IADL)], depression [Patient Depression Questionnaire (PHQ-9) and Centres for Epidemiologic Studies Depression scale (CES-D)], falls and sexual desire. Cognitive impairment was defined using the Frascati criteria, global deficit score (GDS) and multivariate normative comparison (MNC). In the HIV-positive group, the classification performances of the different definitions of cognitive impairment and dichotomized questionnaire results were calculated. RESULTS: The prevalence of cognitive impairment in the HIV-positive group was 34.5% (GDS), 30.0% (Frascati) and 22.1% (MNC), with only 2% diagnosed with HIV-associated dementia. In general, the associations between cognitive impairment and PROMs were weak regardless of the definition used: mean c-statistics were 0.543 (GDS), 0.530 (MNC) and 0.519 (Frascati). Associations were similar using the global T-score to define cognitive impairment. Summary health scores (SF-36) were lower, but only significantly so for those with cognitive impairment identified using MNC, for both mental health (61.4 vs. 75.8; P = 0.03) and physical health (60.9 vs. 75.0; P = 0.03). CONCLUSIONS: The associations between cognitive impairment and PROMs were weak, possibly because impairment was mild and therefore largely asymptomatic. Further work is needed to elucidate the clinical implications of cognitive impairment in HIV-disease.

The role of tenofovir alafenamide in future HIV management.

HIV infection has become a chronic condition rather than an acute life-threatening disease in developed countries, thanks to consistent innovation and evolution of effective interventions. This has altered HIV management and created new challenges. People living with HIV (PLWHIV) are living longer and so encounter comorbidities linked not only with their disease, but also with ageing, lifestyle and chronic exposure to antiretroviral therapy (ART). Although longevity, viral suppression and the prevention of viral transmission remain key goals, more needs to be achieved to encompass the vision of attaining an optimum level of overall health. Treatment choices and management practices should ensure patients' long-term health with minimal comorbidity. Treatments that balance optimal efficacy with the potential for improved long-term safety are needed for all patients. In this review, we consider the evolution and development of tenofovir alafenamide (TAF), a novel prodrug of tenofovir which offers high antiviral efficacy at doses over ten times lower than that of tenofovir disoproxil fumarate (TDF). Emerging clinical data suggest that elvitegravir, cobicistat, emtricitabine and TAF (E/C/F/TAF) as a single-tablet regimen offers highly effective viral suppression in treatment-naïve and treatment-experienced patients with an improved renal and bone safety profile compared with TDF, this having been demonstrated in diverse groups including patients with existing renal impairment and adolescents. The profile of TAF identifies it as an agent with a promising role within future ART regimens that aim to deliver the vision of undetectable viral load, while requiring less monitoring and having a safety profile designed to minimize comorbid risks while supporting good long-term health.

Prognostic impact of discrepant Ki67 and mitotic index on hormone receptor-positive, HER2-negative breast carcinoma.

BACKGROUND: Inconsistencies between mitotic index (MI) and Ki67 measures have been identified in many breast tumour samples. The aim of this study was to describe the prognosis of hormone receptor-positive (HR+) HER2- tumours having discrepant MI and Ki67. METHODS: We included a cohort of breast cancer patients initially treated by surgery between 2001 and 2005 in the Institut Curie. Breast cancer-specific survival (BCSS) and disease-free survival (DFS) were analysed according to three proliferation groups: high MI/high Ki67 (MI=3, Ki67>20%), low MI/low Ki67 (MI<3, Ki67⩽20%) and discrepant (high MI/low Ki67 or low MI/high Ki67). RESULTS: Among the 1430 patients, 19.6% had discrepant Ki67 and MI, 11.6% had high markers and 68.8% had low markers. The 5-year BCSS was 95.8%, 95% CI (0.93-0.98) in the discrepant group, 99.3%, 95% CI (0.993-0.999) in the low-proliferation group and 91.8%, 95% CI (0.88-0.96) in the high-proliferation group. In multivariate analysis, the survival of the discrepant group was lower than that of the low-proliferation group: BCSS hazard ratio (HR)=3.01 (1.32-6.84; P=0.008) and DFS HR=2.07, 95% CI (1.31-3.26; P=0.002). Among grade 2 tumours in multivariate analysis, DFS of the discrepant group was lower than that of the low MI/low Ki67 group: HR=1.98, 95% CI (1.14-3.46), P=0.02. Regarding BCSS, the obtained results were similar. CONCLUSION: The prognosis of patients with discrepant MI and Ki67 appears intermediate between that of low MI/low Ki67 and high MI/high Ki67 groups. These markers should be jointly analysed to clarify prognosis.

Patients Accessing Ambulatory Care for HIV-infection: Epidemiology and Prevalence Assessment.

This study describes the demographics and treatment status of HIV-infected adults accessing ambulatory care in the Republic of Ireland and estimates diagnosed HIV prevalence rates. 3254 HIV-infected adults attended 1 of the 6 specialist HIV centres in the 12- month period 1st July 2009 to 30th June 2010. 2023/3254 (62%) were male, 1761/3133 (56%) Irish and 1048/3133 (34%) African. 1924/3098 (62%) resided in the Dublin area. The mean age was 39.8 years (SD 9.3); probable route of acquisition was available for 2898/3254 (89%); heterosexual acquisition accounted for 1442 (50%), MSM 777 (27%) and IDU 598 (21%). 2574/3202 (80%) were on highly active antiretroviral therapy (HAART). Of these 87% had HIV-RNA levels < 50cpm and 94% < 500cpm. The HIV diagnosed prevalence rate is estimated at 1.09/1000 nationally and at 2.25/1000 in the Dublin area for 15-59 year olds.

Time-varying effect and long-term survival analysis in breast cancer patients treated with neoadjuvant chemotherapy.

BACKGROUND: Recent studies have indicated the prognostic value of tumour subtype and pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). However these results were reported after a short follow-up and using a standard Cox model which could be unsatisfactory for time-dependent factors. In the present study, we identified the prognostic factors for long-term outcome after NAC, considering that they could have an inconstant impact over time. METHODS: Prognostic factors from 956 consecutive breast cancer patients treated with NAC were identified and associated with long-term outcomes. We estimated survival by a time function multivariate Cox model regression and stratified by follow-up length. RESULTS: The prognostic value of tumour histological grade and hormone receptors status varied as distant recurrence-free interval (DRFI) increased. The multivariate analysis identified the following significant prognostic factors: tumour size, N stage, clinical and pathological response to NAC, hormone receptors (HR) status and histological tumour grade. The 'prognostic benefit' of low-grade and positive-HR status decreased over the years. Thus, in the early years after cancer diagnosis, the hazard ratio of distant recurrences in patients with positive-HR status increased from 0.26 (95% CI 0.1-0.4) at 6 months to 2.2 (95% CI 1.3-3.7) at 120 months. The histological tumour grade followed a similar trend. The hazard ratio of grade III patients compared with grade I was 1.83 (95% CI 1.1-2.8) at 36 months and diminished over time to 0.70 (95% CI 0.4-1.3) at 120 months. This indicates that the risk of recurrence for positive-HR patients was 74% lower at 6 months compared with the negative-hormone receptor group, but 30% higher at 5 years and more than double at 10 years. High-grade tumours presented a risk of 83% in the earlier years decreasing to 30% at 10 years versus the low-grade group. CONCLUSION: From the present study, we conclude the importance of identifying time-dependent prognostic factors. Distant recurrence-free interval within women who receive NAC are influenced by achieving pCR and breast cancer subtype. Tumours with more aggressive biology have poorer survival during the first 5 years, but if they exceed this point their prognostic impact is no longer significant. Conversely, positive-HR patients remain at risk for distant recurrence for many years.

Are we able to predict survival in ER-positive HER2-negative breast cancer? A comparison of web-based models.

BACKGROUND: Several prognostic models have been proposed and demonstrated to be predictive of survival outcomes in breast cancer. In the present article, we assessed whether three of these models are comparable at an individual level. METHODS: We used a large data set (n=965) of women with hormone receptor-positive and HER2-negative early breast cancer from the public data set of the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) study. We compared the overall performance of three validated web-based models: Adjuvant!, CancerMath.net and PREDICT, and we assessed concordance of these models in 10-year survival prediction. RESULTS: Discrimination performances of the three calculators to predict 10-year survival were similar for the Adjuvant! Model, 0.74 (95% CI 0.71-0.77) for the Cancermath.net model and 0.72 (95% CI 0.69-0.75) for the PREDICT model). Calibration performances, assessed graphically, were satisfactory. Predictions were concordant and stable in the subgroup, with a predicted survival higher than 90% with a median score dispersion at 0.08 (range 0.06-0.10). Dispersion, however, reached 30% for the subgroups with a predicted survival between 10 and 50%. CONCLUSION: This study revealed that the three web-based predictors equally perform well at the population level, but exhibit a high degree of discordance in the intermediate and poor prognosis groups.

[The role of nipple-sparing mastectomy in breast cancer: a comprehensive review of the literature]. / Mastectomie avec conservation de la plaque aréolo-mamelonnaire et cancer du sein. Mise au point.

BACKGROUND: The role of nipple-sparing mastectomy (NSM) for breast cancer is controversial as there is concern regarding its oncological safety and complication rate. We carried out a review of the literature to quantify the incidence of occult nipple malignancy in breast cancer, identify the factors influencing occult nipple malignancy, quantify locoregional recurrence rates and quantify NSM complication rates. METHODS: A search of the literature was performed using PubMed. Keywords used were "mastectomy", "nipple involvement", "nipple-sparing mastectomy", "skin-sparing mastectomy" "occult nipple malignancy" "occult nipple disease" "breast cancer recurrence". Articles were analyzed regarding incidence of occult nipple malignancy, potential factors influencing the incidence of occult malignancy and recurrence/complications following NSM. The incidence of occult nipple disease was compared between groups using Chi(2) or Fisher's exact tests for categorical variables and Student's t-tests for continuous variables. P values were considered significant<0.05. We identified nearly 30 studies compiling nearly 10 000 cases examining the rate of occult nipple malignancy and 23 studies compiling 2300 cases providing information on the rate of local recurrence after NSM. RESULTS: The overall rate of occult nipple malignancy was 11.5 %. Primary tumour characteristics influencing occult nipple malignancy were tumour-nipple distance<2cm, grade, lymph node metastasis, lymphovascular invasion, HER2 positive, ER/PR negative, tumour size>5cm, retro-areolar/central location and multicentric tumours. The overall nipple recurrence rate following NSM was 0.9 %, skin flap recurrence rate was 4.2 %. Full and partial thickness nipple necrosis rates were 2.9 % and 6.3 % respectively. CONCLUSION: NSM for primary breast cancer is appropriate in carefully selected patients. All patients should have retro-areolar sampling. There is strong evidence to suggest that suitable cases are well circumscribed single or multifocal lesions that have a TND>2cm. Tumours should be graded 1-2 and not have LVI, axillary node metastasis or HER2 positivity.

Histological grade concordance between diagnostic core biopsy and corresponding surgical specimen in HR-positive/HER2-negative breast carcinoma.

BACKGROUND: The identification and validation of suitable predictive and prognostic factors are a challenge to improve the treatment scheme selection. Discordances in histological grade can be established between core biopsy and surgical specimens. This is important in HR-positive/HER2-negative subgroup where histological grade identifies patients at high risk and is a strong determinant for treatment scheme. METHODS: A total of 350 consecutive invasive breast carcinoma biopsies were assessed and compared with surgical specimens in Institut Curie, Paris, France. Clinical, radiological and pathological data were recorded. RESULTS: Histological grade concordance rate in the HR+/HER2- group was 75%. A grade underestimation was mainly due to mitotic index misgrading (23%). Large tumours (P<0.05), premenopausal patients (P=0.005) and non-ultrasound-guided biopsies (P=0.04) were risk factors for misgrading. The highest discordance was found in tumours that required chemotherapy (39%, P<0.05), and it was related to an underestimation of histological grade on core biopsies (94%). CONCLUSIONS: Histological grade in HR+/HER2- group is important to identify patients with poor prognosis and start a systemic therapy. Histological grade discordance was correlated with an underestimation of mitotic index and factors probably associated with intratumor heterogeneity (premenopausal status, tumour size and the type of core biopsy performed). But such discordance did not appear to modify the therapeutic decision, because systemic treatment decision-making also integrates other variables. Determining histological grade in core biopsy can be especially important in HR-positive/HER2-negative subgroup where it identifies patients at high risk and is a strong determinant of the treatment scheme.