Ductal carcinoma in situ and cause-specific mortality among younger and older postmenopausal women: the Women's Health Initiative.

BACKGROUND: Whether DCIS is associated with higher breast cancer-specific and all-cause mortality is unclear with few studies in older women. Therefore, we examined DCIS and breast cancer-specific, cardiovascular (CVD)-specific, and all-cause mortality among Women's Health Initiative (WHI) Clinical Trial participants overall and by age (< 70 versus ≥ 70 years). METHODS: Of 68,132 WHI participants, included were 781 postmenopausal women with incident DCIS and 781 matched controls. Serial screening mammography was mandated with high adherence. DCIS cases were confirmed by central medical record review. Adjusted multivariable Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Kaplan Meier (KM) plots were used to assess 10-year and 20-year mortality rates. RESULTS: After 20.3 years total, and 13.2 years median post-diagnosis follow-up, compared to controls, DCIS was associated with higher breast cancer-specific mortality (HR 3.29; CI = 1.32-8.22, P = 0.01). The absolute difference in 20-year breast cancer mortality was 1.2% without DCIS and 3.4% after DCIS, log-rank P = 0.026. Findings were similar by age (< 70 versus ≥ 70 years) with no interaction (P interaction = 0.80). Incident DCIS was not associated with CVD-specific mortality (HR 0.77; CI-0.54-1.09, P = 0.14) or with all-cause mortality (HR 0.96; CI = 0.80-1.16, P = 0.68) with similar findings by age. CONCLUSIONS: In postmenopausal women, incident DCIS was associated with over three-fold higher breast cancer-specific mortality, with similar findings in younger and older postmenopausal women. These finding suggest caution in using age to adjust DCIS clinical management or research strategies.

Temporal changes in mammographic breast density and breast cancer risk among women with benign breast disease.

INTRODUCTION: Benign breast disease (BBD) and high mammographic breast density (MBD) are prevalent and independent risk factors for invasive breast cancer. It has been suggested that temporal changes in MBD may impact future invasive breast cancer risk, but this has not been studied among women with BBD. METHODS: We undertook a nested case-control study within a cohort of 15,395 women with BBD in Kaiser Permanente Northwest (KPNW; 1970-2012, followed through mid-2015). Cases (n = 261) developed invasive breast cancer > 1 year after BBD diagnosis, whereas controls (n = 249) did not have breast cancer by the case diagnosis date. Cases and controls were individually matched on BBD diagnosis age and plan membership duration. Standardized %MBD change (per 2 years), categorized as stable/any increase (≥ 0%), minimal decrease of less than 5% or a decrease greater than or equal to 5%, was determined from baseline and follow-up mammograms. Associations between MBD change and breast cancer risk were examined using adjusted unconditional logistic regression. RESULTS: Overall, 64.5% (n = 329) of BBD patients had non-proliferative and 35.5% (n = 181) had proliferative disease with/without atypia. Women with an MBD decrease (≤ - 5%) were less likely to develop breast cancer (Odds Ratio (OR) 0.64; 95% Confidence Interval (CI) 0.38, 1.07) compared with women with minimal decreases. Associations were stronger among women ≥ 50 years at BBD diagnosis (OR 0.48; 95% CI 0.25, 0.92) and with proliferative BBD (OR 0.32; 95% CI 0.11, 0.99). DISCUSSION: Assessment of temporal MBD changes may inform risk monitoring among women with BBD, and strategies to actively reduce MBD may help decrease future breast cancer risk.

Examining the impact of COVID-19 disruptions on population-based breast cancer screening in Ireland.

OBJECTIVE: Many population-based breast screening programmes temporarily suspended routine screening following the COVID-19 pandemic onset. This study aimed to describe screening mammography utilisation and the pattern of screen-detected breast cancer diagnoses following COVID-19-related screening disruptions in Ireland. METHODS: Using anonymous aggregate data from women invited for routine screening, three time periods were examined: (1) January-December 2019, (2) January-December 2020, and (3) January-December 2021. Descriptive statistics were conducted and comparisons between groups were performed using chi-square tests. RESULTS: In 2020, screening mammography capacity fell by 67.1% compared to 2019; recovering to 75% of mammograms performed in 2019, during 2021. Compared to 2019, for screen-detected invasive breast cancers, a reduction in Grade 1 (14.2% vs. 17.2%) and Grade 2 tumours (53.4% vs. 58.0%) and an increase in Grade 3 tumours (32.4% vs. 24.8%) was observed in 2020 (p = 0.03); whereas an increase in Grade 2 tumours (63.3% vs. 58.0%) and a reduction in Grade 3 tumours (19.6% vs. 24.8%) was found in 2021 (p = 0.02). No changes in oestrogen receptor-positive or nodal-positive diagnoses were observed; however the proportion of oestrogen/progesterone receptor-positive breast cancers significantly increased in 2020 (76.2%; p < 0.01) and 2021 (78.7%; p < 0.001) compared to 2019 (67.8%). CONCLUSION: These findings demonstrate signs of a grade change for screen-detected invasive breast cancers early in the pandemic, with recovery evident in 2021, and without an increase in nodal positivity. Future studies are needed to determine the COVID-19 impact on long-term breast cancer outcomes including mortality.

Dealing with digital paralysis: Surviving a cyberattack in a National Cancer center.

INTRODUCTION: Cyberattacks represent a growing threat for healthcare delivery globally. We assess the impact and implications of a cyberattack on a cancer center in Ireland. METHODS: On May 14th 2021 (day 0) Cork University Hospital (CUH) Cancer Center was involved in the first national healthcare ransomware attack in Ireland. Contingency plans were only present in laboratory services who had previously experienced information technology (IT) failures. No hospital cyberattack emergency plan was in place. Departmental logs of activity for 120 days after the attack were reviewed and compared with historical activity records. Daily sample deficits (routine daily number of samples analyzed - number of samples analyzed during cyberattack) were calculated. Categorical variables are reported as median and range. Qualitative data were collected via reflective essays and interviews with key stakeholders from affected departments in CUH. RESULTS: On day 0, all IT systems were shut down. Radiotherapy (RT) treatment and cancer surgeries stopped, outpatient activity fell by 50%. hematology, biochemistry and radiology capacity fell by 90% (daily sample deficit (DSD) 2700 samples), 75% (DSD 2250 samples), and 90% (100% mammography/PET scan) respectively. Histopathology reporting times doubled (7 to 15 days). Radiotherapy (RT) was interrupted for 113 patients in CUH. The median treatment gap duration was six days for category 1 patients and 10 for the remaining patients. Partner organizations paused all IT links with CUH. Outsourcing of radiology and radiotherapy commenced, alternative communication networks and national conference calls in RT and Clinical Trials were established. By day 28 Email communication was restored. By day 210 reporting and data storage backlogs were cleared and over 2000 computers were checked/replaced. CONCLUSION: Cyberattacks have rapid, profound and protracted impacts. While laboratory and diagnostic deficits were readily quantified, the impact of disrupted/delayed care on patient outcomes is less readily quantifiable. Cyberawareness and cyberattack plans need to be embedded in healthcare. POLICY SUMMARY: Cyberattacks pose significant challenges for healthcare systems, impacting patient care, clinical outcomes, and staff wellbeing. This study provides a comprehensive review of the impact of the Conti ransomware attack on cancer services in Cork University Hospital (CUH), the first cyberattack on a national health service. Our study highlights the widespread disruption caused by a cyberattack including shutdown of information technology (IT) services, marked reduction in outpatient activity, temporary cessation of essential services such as radiation therapy. We provide a framework for other institutions for mitigating the impact of a cyberattack, underscoring the need for a cyberpreparedness plan similar to those made for natural disasters and the profound legacy of a cyberattack on patient care.

Risk of COVID-19 death for people with a pre-existing cancer diagnosis prior to COVID-19-vaccination: A systematic review and meta-analysis.

While previous reviews found a positive association between pre-existing cancer diagnosis and COVID-19-related death, most early studies did not distinguish long-term cancer survivors from those recently diagnosed/treated, nor adjust for important confounders including age. We aimed to consolidate higher-quality evidence on risk of COVID-19-related death for people with recent/active cancer (compared to people without) in the pre-COVID-19-vaccination period. We searched the WHO COVID-19 Global Research Database (20 December 2021), and Medline and Embase (10 May 2023). We included studies adjusting for age and sex, and providing details of cancer status. Risk-of-bias assessment was based on the Newcastle-Ottawa Scale. Pooled adjusted odds or risk ratios (aORs, aRRs) or hazard ratios (aHRs) and 95% confidence intervals (95% CIs) were calculated using generic inverse-variance random-effects models. Random-effects meta-regressions were used to assess associations between effect estimates and time since cancer diagnosis/treatment. Of 23 773 unique title/abstract records, 39 studies were eligible for inclusion (2 low, 17 moderate, 20 high risk of bias). Risk of COVID-19-related death was higher for people with active or recently diagnosed/treated cancer (general population: aOR = 1.48, 95% CI: 1.36-1.61, I2 = 0; people with COVID-19: aOR = 1.58, 95% CI: 1.41-1.77, I2 = 0.58; inpatients with COVID-19: aOR = 1.66, 95% CI: 1.34-2.06, I2 = 0.98). Risks were more elevated for lung (general population: aOR = 3.4, 95% CI: 2.4-4.7) and hematological cancers (general population: aOR = 2.13, 95% CI: 1.68-2.68, I2 = 0.43), and for metastatic cancers. Meta-regression suggested risk of COVID-19-related death decreased with time since diagnosis/treatment, for example, for any/solid cancers, fitted aOR = 1.55 (95% CI: 1.37-1.75) at 1 year and aOR = 0.98 (95% CI: 0.80-1.20) at 5 years post-cancer diagnosis/treatment. In conclusion, before COVID-19-vaccination, risk of COVID-19-related death was higher for people with recent cancer, with risk depending on cancer type and time since diagnosis/treatment.

A scoping review of programme specific mammographic breast density related guidelines and practices within breast screening programmes.

Introduction: High mammographic breast density (MBD) is an independent breast cancer risk factor. In organised breast screening settings, discussions are ongoing regarding the optimal clinical role of MBD to help guide screening decisions. The aim of this scoping review was to provide an overview of current practices incorporating MBD within population-based breast screening programmes and from professional organisations internationally. Methods: This scoping review was conducted in accordance with the framework proposed by the Joanna Briggs Institute. The electronic databases, MEDLINE (PubMed), EMBASE, CINAHL Plus, Scopus, and Web of Science were systematically searched. Grey literature sources, websites of international breast screening programmes, and relevant government organisations were searched to identify further relevant literature. Data from identified materials were extracted and presented as a narrative summary. Results: The search identified 78 relevant documents. Documents were identified for breast screening programmes in 18 countries relating to screening intervals for women with dense breasts, MBD measurement, reporting, notification, and guiding supplemental screening. Documents were identified from 18 international professional organisations with the majority of material relating to supplemental screening guidance for women with dense breasts. Key factors collated during the data extraction process as relevant considerations for MBD practices included the evidence base needed to inform decision-making processes and resources (healthcare system costs, radiology equipment, and workforce planning). Conclusions: This scoping review summarises current practices and guidelines incorporating MBD in international population-based breast screening settings and highlights the absence of consensus between organised breast screening programmes incorporating MBD in current breast screening protocols.

Short-term changes in ultrasound tomography measures of breast density and treatment-associated endocrine symptoms after tamoxifen therapy.

Although breast density decline with tamoxifen therapy is associated with greater therapeutic benefit, limited data suggest that endocrine symptoms may also be associated with improved breast cancer outcomes. However, it is unknown whether endocrine symptoms are associated with reductions in breast density after tamoxifen initiation. We evaluated treatment-associated endocrine symptoms and breast density change among 74 women prescribed tamoxifen in a 12-month longitudinal study. Treatment-associated endocrine symptoms and sound speed measures of breast density, assessed via novel whole breast ultrasound tomography (m/s), were ascertained before tamoxifen (T0) and at 1-3 (T1), 4-6 (T2), and 12 months (T3) after initiation. CYP2D6 status was genotyped, and tamoxifen metabolites were measured at T3. Using multivariable linear regression, we estimated mean change in breast density by treatment-associated endocrine symptoms adjusting for age, race, menopausal status, body mass index, and baseline density. Significant breast density declines were observed in women with treatment-associated endocrine symptoms (mean change (95% confidence interval) at T1:-0.26 m/s (-2.17,1.65); T2:-2.12 m/s (-4.02,-0.22); T3:-3.73 m/s (-5.82,-1.63); p-trend = 0.004), but not among women without symptoms (p-trend = 0.18) (p-interaction = 0.02). Similar declines were observed with increasing symptom frequency (p-trends for no symptoms = 0.91; low/moderate symptoms = 0.03; high symptoms = 0.004). Density declines remained among women with detectable tamoxifen metabolites or intermediate/efficient CYP2D6 metabolizer status. Emergent/worsening endocrine symptoms are associated with significant, early declines in breast density after tamoxifen initiation. Further studies are needed to assess whether these observations predict clinical outcomes. If confirmed, endocrine symptoms may be a proxy for tamoxifen response and useful for patients and providers to encourage adherence.

Impact of the COVID-19 pandemic on cancer care in Ireland - Perspectives from a COVID-19 and Cancer Working Group.

Upon the COVID-19 pandemic onset in Ireland, cancer service disruptions occurred due to prioritisation of COVID-19 related care, redeployment of staff, initial pausing of screening, diagnostic, medical and surgical oncology procedures, staff shortages due to COVID-19 infection and impacts on the physical and mental health of cancer healthcare workers. This was coupled with reluctance among people with symptoms suspicious for cancer to attend for clinical evaluation, due to concerns of contracting the virus. This was further compounded by a cyber-attack on national health service IT systems on May 14th 2021. The Irish Cancer Society, a national cancer charity with a role in advocacy, research and patient supports, convened a multi-disciplinary stakeholder group (COVID-19 and Cancer Working Group) to reflect on and understand the impact of the pandemic on cancer patients and services in Ireland, and discuss potential mitigation strategies. Perspectives on experiences were gathered across domains including timeliness of data acquisition and its conversion into intelligence, and the resourcing of cancer care to address cancer service impacts. The group highlighted aspects for future research to understand the long-term pandemic impact on cancer outcomes, while also highlighting potential strategies to support cancer services, build resilience and address delayed diagnosis. Additional measures include the need for cancer workforce recruitment and retention, increased mental health supports for both patients and oncology professionals, improvements to public health messaging, a near real-time multimodal national cancer database, and robust digital and physical infrastructure to mitigate impacts of the current pandemic and future challenges to cancer care systems.

Vitamin D Supplementation: Does It Have a Preventative or Therapeutic Role in Cancer?

Although best known for its role in skeletal health, a deficiency of vitamin D has also been implicated in cancer formation and progression. The aim of this article was to review the relationship between circulating levels of vitamin D {25(OH)D} and both the risk of developing cancer and outcome from cancer. We also reviewed the effects of vitamin D supplementation on cancer risk and outcome. Our primary focus was on patients with colorectal and breast cancer, as these are two of the cancer types best investigated with respect to the effects of vitamin D on cancer risk and outcome. Based on our review of the literature, we conclude that although low circulating levels of 25(OH)D appears to be associated with an increased risk of developing breast and colorectal cancer, the available evidence suggests that supplementation of healthy subjects with vitamin D does not decrease cancer risk. Supplementation may however, improve outcomes in patients who develop cancer, but this finding remains to be confirmed in an appropriately powered randomized clinical trial.

Evaluating awareness, knowledge and practice of healthcare professionals following implementation of a revised pregnancy prevention programme for isotretinoin in Ireland: A multi-stakeholder cross-sectional study.

PURPOSE: In 2018, following an EU-wide safety review, a revised pregnancy prevention programme (PPP) was introduced for isotretinoin (Roaccutane®). This study aimed to examine awareness, knowledge, and experience implementing the revised isotretinoin PPP in clinical practice across three healthcare professional (HCP) groups in Ireland. METHODS: A cross-sectional study using anonymous online surveys among general practitioners (GPs), community pharmacists, and specialist consultants was undertaken. Descriptive analyses are presented. RESULTS: Across all HCP groups there was high (≥87%) awareness that oral isotretinoin is contraindicated in women of childbearing potential (WCBP) unless the conditions of the PPP are fulfilled, but varying awareness among GPs (54.9%) and community pharmacists (45.9%) that exposure during pregnancy can cause both severe fetal malformations and spontaneous abortions. Implementation of the PPP in clinical practice varied across HCP groups. When initiating isotretinoin in WCBP, 66.7% of specialists and 40.8% of GPs indicated they had considered alternative treatment options, and 71.4% of specialists and 31.6% of GPs reported they first requested a pregnancy test. There was limited provision of the patient reminder card to WCBP, where 26.1% of community pharmacists provide this at each dispensing, while 47.6% of specialists and 11.8% of GPs ensured WCBP had a copy of the card when initiating treatment. Across all HCP groups, there was high (≥81.6%) awareness of the need for urgent consultation and immediate cessation of isotretinoin in the event of an unplanned or suspected pregnancy. CONCLUSIONS: Reinforcement of the provision and utilisation of the isotretinoin patient reminder card may be required, and further targeted education on specific elements of the PPP should be considered for GPs and community pharmacists.

Mammographic Density Decline, Tamoxifen Response, and Prognosis by Molecular Characteristics of Estrogen Receptor-Positive Breast Cancer.

BACKGROUND: Mammographic breast density (MBD) decline post-tamoxifen initiation is a favorable prognostic factor in estrogen receptor (ER)-positive breast cancer (BC) and has potential utility as a biomarker of tamoxifen response. However, the prognostic value of MBD decline may vary by molecular characteristics among ER-positive patients. METHODS: We investigated associations between MBD decline (≥10% vs <10%) and breast cancer-specific mortality (BCSM) among ER-positive breast cancer patients aged 36-87 years at diagnosis treated with tamoxifen at Kaiser Permanente Northwest (1990-2008). Patients who died of BC (case patients; n = 62) were compared with those who did not (control patients; n = 215) overall and by tumor molecular characteristics (immunohistochemistry [IHC]-based subtype [luminal A-like: ER-positive/progesterone receptor [PR]-positive/HER2-negative/low Ki67; luminal B-like: ER-positive and 1 or more of PR-negative, HER2-positive, high Ki67] and modified IHC [mIHC]-based recurrence score of ER/PR/Ki67). Percent MBD was measured in the unaffected breast at baseline mammogram (mean = 6 months before tamoxifen initiation) and follow-up (mean = 12 months post-tamoxifen initiation). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed from logistic regression models. All statistical tests were 2-sided. RESULTS: MBD decline was statistically significantly associated with reduced risk of BCSM overall (OR = 0.38, 95% CI = 0.15 to 0.92). This association was, however, stronger among women with aggressive tumor characteristics including luminal B-like (OR = 0.17, 95% CI = 0.04 to 0.73) vs A-like (OR = 0.74, 95% CI = 0.19 to 2.92); large (OR = 0.26, 95% CI = 0.08 to 0.78) vs small (OR = 0.41, 95% CI = 0.04 to 3.79) tumors; PR-negative (OR = 0.02, 95% CI = 0.001 to 0.37) vs PR-positive (OR = 0.50, 95% CI = 0.18 to 1.40) disease; and high (OR = 0.25, 95% CI = 0.07 to 0.93) vs low (OR = 0.44, 95% CI = 0.10 to 2.09) mIHC3 score. CONCLUSION: The findings support MBD decline as a prognostic marker of tamoxifen response among patients with aggressive ER-positive BC phenotypes, for whom understanding treatment effectiveness is critical.

Valproate utilisation trends among women of childbearing potential in Ireland between 2014 and 2019: A drug utilisation study using interrupted time series.

PURPOSE: This study aimed to examine trends in valproate use among women of childbearing potential (WCBP) aged 16-44 years in Ireland following two European-directed regulatory interventions in December 2014 and April 2018. METHODS: This was a repeated cross-sectional study using monthly national pharmacy claims data, to examine trend changes in the prevalence of valproate use among WCBP pre and post two separate regulatory events in December 2014 and April 2018. Annual population estimates from the Central Statistics Office were used to calculate the prevalence rate per 1000 eligible women. Segmented regression analysis of interrupted time series with negative binomial regression was used to examine rates for WCBP aged 16-44 years, and by 10-year age groups. Prevalence ratios (PR) are presented with 95% confidence intervals (CIs). RESULTS: Among WCBP aged 16-44 years, there was no statistically significant change in the month-to-month prevalence ratio in the post- compared to pre-December 2014 intervention period. A significant decline was, however, observed in the post-, compared to pre-April 2018 intervention period (PR = 0.998, [95% CIs: 0.996, 1.000]; p = 0.029). Among those aged 16-24 years, a significant decreasing trend in the month-to-month prevalence ratio was found in the post- compared to pre-December 2014 intervention period (PR = 0.991, [95% CIs: 0.984, 0.998];p <0.01). A marginal effect was observed in the post- compared to pre-April 2018 intervention period for those aged 25-34 years (PR = 0.996, [95% CIs: 0.992, 1.000]; p = 0.048). CONCLUSION: Although no evidence of change was observed following the December 2014 intervention period, a significant decline in the prevalence ratio of valproate use was observed after the 2018 intervention, which may reflect the introduction of the most recent contraindication measures.

Mammary collagen architecture and its association with mammographic density and lesion severity among women undergoing image-guided breast biopsy.

BACKGROUND: Elevated mammographic breast density is a strong breast cancer risk factor with poorly understood etiology. Increased deposition of collagen, one of the main fibrous proteins present in breast stroma, has been associated with increased mammographic density. Collagen fiber architecture has been linked to poor outcomes in breast cancer. However, relationships of quantitative collagen fiber features assessed in diagnostic biopsies with mammographic density and lesion severity are not well-established. METHODS: Clinically indicated breast biopsies from 65 in situ or invasive breast cancer cases and 73 frequency matched-controls with a benign biopsy result were used to measure collagen fiber features (length, straightness, width, alignment, orientation and density (fibers/µm2)) using second harmonic generation microscopy in up to three regions of interest (ROIs) per biopsy: normal, benign breast disease, and cancer. Local and global mammographic density volumes were quantified in the ipsilateral breast in pre-biopsy full-field digital mammograms. Associations of fibrillar collagen features with mammographic density and severity of biopsy diagnosis were evaluated using generalized estimating equation models with an independent correlation structure to account for multiple ROIs within each biopsy section. RESULTS: Collagen fiber density was positively associated with the proportion of stroma on the biopsy slide (p < 0.001) and with local percent mammographic density volume at both the biopsy target (p = 0.035) and within a 2 mm perilesional ring (p = 0.02), but not with global mammographic density measures. As severity of the breast biopsy diagnosis increased at the ROI level, collagen fibers tended to be less dense, shorter, straighter, thinner, and more aligned with one another (p < 0.05). CONCLUSIONS: Collagen fiber density was positively associated with local, but not global, mammographic density, suggesting that collagen microarchitecture may not translate into macroscopic mammographic features. However, collagen fiber features may be markers of cancer risk and/or progression among women referred for biopsy based on abnormal breast imaging.

Awareness, knowledge and practice of healthcare professionals following implementation of a Pregnancy Prevention Program for sodium valproate in Ireland: a multi-stakeholder cross-sectional study.

OBJECTIVES: To establish awareness, knowledge, use and experience in practice of a sodium valproate pregnancy prevention program (PPP) in Ireland ("prevent") among three healthcare professional (HCP) groups. METHODS: A cross-sectional study using anonymous online surveys was conducted among general practitioners (GPs), pharmacists, and specialist consultants. Descriptive analyses are presented. RESULTS: HCP response rates were 5.8% for GPs (90/1544), 10.7% for pharmacists (219/2052), and 7.6% for specialists (17/224). Across HCP groups, there was high awareness (>90%) for specialist referral when female valproate patients are planning pregnancy, or become pregnant, but less awareness to refer annually for specialist review. While awareness of a possible teratogenic effect at any stage of pregnancy was high (>80%), most GPs (62.2%, 95% CI: 51.3, 71.9%) and community pharmacists (53.1%, 95% CI: 43.2, 62.8%) were unsure of the magnitude of risk for developmental disorders, while most specialists under-estimated this risk (46.7%, 95% CI: 24.8, 69.9%). Although >70% of the respondents identified valproate to be contraindicated in any woman of childbearing potential unless the conditions of the PPP are fulfilled, experience implementing key elements in practice varied. CONCLUSIONS: Our findings suggest continued effort is needed to ensure optimal implementation of "prevent" into clinical practice in Ireland.

Underlying conditions and risk of hospitalisation, ICU admission and mortality among those with COVID-19 in Ireland: A national surveillance study.

BACKGROUND: To date, over 2 million people worldwide have died with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To describe the experience in Ireland, this study examined associations between underlying conditions and the following outcomes: mortality, admission to hospital or admission to the intensive care unit (ICU) among those infected with COVID-19. METHODS: This study used data from the Health Protection Surveillance Centre in Ireland and included confirmed cases of COVID-19 from the first wave of the pandemic between March and July 2020. Two cohorts were included: all cases (community and hospital) and hospital admissions only. For all cases, health outcome data included mortality and hospitalisation. For hospitalised cases, outcome data included mortality and ICU admission. Logistic regression was used to examine associations between underlying conditions and outcomes across both cohorts. Results are presented as adjusted odds ratios (OR) and 95% confidence intervals (CIs). FINDINGS: There were 19,789 cases included in analysis, which encompassed 1,476 (7.5%) deaths, 2,811 (14.2%) hospitalisations, and 438 (2.2%) ICU admissions of whom 90 (20.5%) died. Significantly higher risk of mortality, hospitalisation and ICU admission was associated with having chronic heart disease, a BMI ≥40kg/m2 and male sex. Additionally, diagnosis of a chronic neurological condition (OR 1.41; 95%CI:1.17, 1.69), chronic kidney disease (OR 1.74; 95%CI:1.35, 2.24) and cancer (OR 2.77; 95%CI:2.21, 3.47) were significantly associated with higher risk of mortality among all cases, with similar patterns of association observed for mortality among hospitalised cases. INTERPRETATION: The identification of underlying conditions among COVID-19 cases may help identify those at highest risk of the worst health outcomes and inform preventive strategies to improve outcomes. FUNDING: This study was supported by the Health Service Executive, Health Protection Surveillance Centre. KEB and MM are funded by the Health Research Board (RL-15-1579 and EIA-2019-012 respectively).

Risk factors for contralateral breast cancer in postmenopausal breast cancer survivors in the NIH-AARP Diet and Health Study.

PURPOSE: The role of established breast cancer risk factors and clinical characteristics of the first breast cancer in the development of contralateral breast cancer (CBC) among postmenopausal women is unclear. METHODS: We identified 10,934 postmenopausal women diagnosed with a first primary breast cancer between 1995 and 2011 in the NIH-AARP Diet and Health Study. CBC was defined as a second primary breast cancer diagnosed in the contralateral breast ≥ 3 months after the first breast cancer. Exposures included pre-diagnosis risk factors (lifestyle, reproductive, family history) and clinical characteristics of the first breast cancer. We used multivariable Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Over a median follow-up of 6.8 years, 436 women developed CBC. We observed an increasing trend in CBC risk by age (p-trend = 0.002) and decreasing trend by year of diagnosis (p-trend = 0.001) of the first breast cancer. Additional risk factor associations were most pronounced for endocrine therapy (HR 0.68, 95% CI 0.53-0.87) and family history of breast cancer (HR 1.38, 95% CI 1.06-1.80, restricted to invasive first breast cancer). No associations were found for lifestyle (body mass index, physical activity, smoking, alcohol) or reproductive factors (age at menarche, parity, age at first birth, age at menopause). CONCLUSIONS: This study suggests that clinical characteristics of the first breast cancer and family history of breast cancer, but not pre-diagnosis lifestyle and reproductive factors, are strongly associated with CBC risk among postmenopausal women. Future studies are needed to understand how these factors contribute to CBC etiology and to identify further opportunities for prevention.

Retrospective radiological review and classification of interval breast cancers within population-based breast screening programmes for the purposes of open disclosure: A systematic review.

INTRODUCTION: Interval breast cancers occur following a negative breast screening mammogram and before the next scheduled appointment within screening programmes. Radiological review classifies them as cancers that develop between screens, cancers with no obvious malignant abnormalities on prior screens or cancers not detected at screening. This study aimed to systematically review published literature on the occurrence of open disclosure following interval cancer radiological reviews by breast screening programmes internationally in a retrospective setting and examine methodologies used for radiological reviews for the purposes of disclosure. METHODS: A search for relevant articles published (January 2000 - May 2019) was conducted according to PICO and PRISMA guidelines. The databases Pubmed, Scopus, Google Scholar, Cinahl, Web of Science, Embase, Science Direct and Global Health were searched. Relevant studies were reviewed if they had completed a retrospective review and classification of interval breast cancers. RESULTS: Of 46 relevant articles included, no study was identified that conducted a retrospective review purposely for open disclosure. Retrospective reviews were conducted for audit/quality assurance, and research including for radiologist education and learning. Variation in methodology was found across review type (non-blinded/semi-informed approach), number of reviewers and classification categories. The proportion of false negative cancers classified among the studies ranged from 4 to 40 %. DISCUSSION: Variation among radiological review practices were observed, which likely impacts classification results. To ensure standardised classification of interval breast cancers are employed for the purposes of open disclosure in screening settings, reproducible and consistent methodology is required.

Association of lifestyle and clinical characteristics with receipt of radiotherapy treatment among women diagnosed with DCIS in the NIH-AARP Diet and Health Study.

PURPOSE: The long-term risks and benefits of radiotherapy for ductal carcinoma in situ (DCIS) remain unclear. Recent data from the Surveillance, Epidemiology and End Results (SEER) registries showed that DCIS-associated radiotherapy treatment significantly increased risk of second non-breast cancers including lung cancer. To help understand those observations and whether breast cancer risk factors are related to radiotherapy treatment decision-making, we examined associations between lifestyle and clinical factors with DCIS radiotherapy receipt. METHODS: Among 1628 participants from the NIH-AARP Diet and Health Study, diagnosed with incident DCIS (1995-2011), we examined associations between lifestyle and clinical factors with radiotherapy receipt. Radiotherapy and clinical information were ascertained from state cancer registries. Odds ratios (ORs) and 95% confidence intervals (CIs) for radiotherapy receipt (yes/no) were estimated from multivariable logistic regression. RESULTS: Overall, 45% (n = 730) received radiotherapy. No relationships were observed for most lifestyle factors and radiotherapy receipt, including current smoking (OR 0.97, 95%CI 0.70, 1.34). However positive associations were observed for moderate alcohol consumption and infrequent physical activity. The strongest associations were observed for radiotherapy receipt and more recent diagnoses (2005-2011 vs. 1995-1999; OR 1.60, 95%CI 1.14, 2.25), poorly versus well-differentiated tumors (OR 1.69, 95%CI 1.16, 2.46) and endocrine therapy (OR 3.37, 95%CI 2.56, 4.44). CONCLUSIONS: Clinical characteristics were the strongest determinants of DCIS radiotherapy. Receipt was largely unrelated to lifestyle factors suggesting that the previously observed associations in SEER were likely not confounded by these lifestyle factors. Further studies are needed to understand mechanisms driving radiotherapy-associated second malignancies following DCIS, to identify prevention opportunities for this growing population.

Application of convolutional neural networks to breast biopsies to delineate tissue correlates of mammographic breast density.

Breast density, a breast cancer risk factor, is a radiologic feature that reflects fibroglandular tissue content relative to breast area or volume. Its histology is incompletely characterized. Here we use deep learning approaches to identify histologic correlates in radiologically-guided biopsies that may underlie breast density and distinguish cancer among women with elevated and low density. We evaluated hematoxylin and eosin (H&E)-stained digitized images from image-guided breast biopsies (n = 852 patients). Breast density was assessed as global and localized fibroglandular volume (%). A convolutional neural network characterized H&E composition. In total 37 features were extracted from the network output, describing tissue quantities and morphological structure. A random forest regression model was trained to identify correlates most predictive of fibroglandular volume (n = 588). Correlations between predicted and radiologically quantified fibroglandular volume were assessed in 264 independent patients. A second random forest classifier was trained to predict diagnosis (invasive vs. benign); performance was assessed using area under receiver-operating characteristics curves (AUC). Using extracted features, regression models predicted global (r = 0.94) and localized (r = 0.93) fibroglandular volume, with fat and non-fatty stromal content representing the strongest correlates, followed by epithelial organization rather than quantity. For predicting cancer among high and low fibroglandular volume, the classifier achieved AUCs of 0.92 and 0.84, respectively, with epithelial organizational features ranking most important. These results suggest non-fatty stroma, fat tissue quantities and epithelial region organization predict fibroglandular volume. The model holds promise for identifying histological correlates of cancer risk in patients with high and low density and warrants further evaluation.

Involution of Breast Lobules, Mammographic Breast Density and Prognosis Among Tamoxifen-Treated Estrogen Receptor-Positive Breast Cancer Patients.

Mammographic breast density (MD) reflects breast fibroglandular content. Its decline following adjuvant tamoxifen treated, estrogen receptor (ER)-positive breast cancer has been associated with improved outcomes. Breast cancers arise from structures termed lobules, and lower MD is associated with increased age-related lobule involution. We assessed whether pre-treatment involution influenced associations between MD decline and risk of breast cancer-specific death. ER-positive tamoxifen treated patients diagnosed at Kaiser Permanente Northwest (1990-2008) were defined as cases who died of breast cancer (n = 54) and matched controls (remained alive over similar follow-up; n = 180). Lobule involution was assessed by examining terminal duct lobular units (TDLUs) in benign tissues surrounding cancers as TDLU count/mm2, median span and acini count/TDLU. MD (%) was measured in the unaffected breast at baseline (median 6-months before) and follow-up (median 12-months after tamoxifen initiation). TDLU measures and baseline MD were positively associated among controls (p < 0.05). In multivariable regression models, MD decline (≥10%) was associated with reduced risk of breast cancer-specific death before (odds ratio (OR): 0.41, 95% CI: 0.18-0.92) and after (OR: 0.41, 95% CI: 0.18-0.94) adjustment for TDLU count/mm2, TDLU span (OR: 0.34, 95% CI: 0.14-0.84), and acini count/TDLU (OR: 0.33, 95% CI: 0.13-0.81). MD decline following adjuvant tamoxifen is associated with reduced risk of breast cancer-specific death, irrespective of pre-treatment lobule involution.