Immune cell infiltrate in ductal carcinoma in situ and the risk of dying from breast cancer: case-control study.

BACKGROUND: Studies identifying risk factors for death from breast cancer after ductal carcinoma in situ (DCIS) are rare. In this retrospective nested case-control study, clinicopathological factors in women treated for DCIS and who died from breast cancer were compared with those of patients with DCIS who were free from metastatic disease. METHODS: The study included patients registered with DCIS without invasive carcinoma in Sweden between 1992 and 2012. This cohort was linked to the National Cause of Death Registry. Of 6964 women with DCIS, 96 were registered with breast cancer as cause of death (cases). For each case, up to four controls (318; women with DCIS, alive and without metastatic breast cancer at the time of death of the corresponding case) were selected randomly by incidence density sampling. Whole slides of tumour tissue were evaluated for DCIS grade, comedo necrosis, and intensity of periductal lymphocytic infiltrate. Composition of the immune cell infiltrate, expression of oestrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and proliferation marker Ki-67 were scored on tissue microarrays. Clinical information was obtained from medical records. Information on date, site, and histological characteristics of local and distant recurrences was obtained from medical records for both cases and controls. RESULTS: Tumour tissue was analysed from 65 cases and 195 controls. Intense periductal lymphocytic infiltrate around DCIS was associated with an increased risk of later dying from breast cancer (OR 2.21. 95% c.i. 1.01 to 4.84). Tumours with more intense lymphocytic infiltrate had a lower T cell/B cell ratio. None of the other biomarkers correlated with increased risk of breast cancer death. CONCLUSION: The immune response to DCIS may influence the risk of dying from breast cancer.

Prognostic impact of HER2 biomarker levels in trastuzumab-treated early HER2-positive breast cancer.

BACKGROUND: Overexpression of human epidermal growth factor receptor 2 (HER2) caused by HER2 gene amplification is a driver in breast cancer tumorigenesis. We aimed to investigate the prognostic significance of manual scoring and digital image analysis (DIA) algorithm assessment of HER2 copy numbers and HER2/CEP17 ratios, along with ERBB2 mRNA levels among early-stage HER2-positive breast cancer patients treated with trastuzumab. METHODS: This retrospective study comprised 371 early HER2-positive breast cancer patients treated with adjuvant trastuzumab, with HER2 re-testing performed on whole tumor sections. Digitized tumor tissue slides were manually scored and assessed with uPath HER2 Dual ISH image analysis, breast algorithm. Targeted ERBB2 mRNA levels were assessed by the Xpert® Breast Cancer STRAT4 Assay. HER2 copy number and HER2/CEP17 ratio from in situ hybridization assessment, along with ERBB2 mRNA levels, were explored in relation to recurrence-free survival (RFS). RESULTS: The analysis showed that patients with tumors with the highest and lowest manually counted HER2 copy number levels had worse RFS than those with intermediate levels (HR = 2.7, CI 1.4-5.3, p = 0.003 and HR = 2.1, CI 1.1-3.9, p = 0.03, respectively). A similar trend was observed for HER2/CEP17 ratio, and the DIA algorithm confirmed the results. Moreover, patients with tumors with the highest and the lowest values of ERBB2 mRNA had a significantly worse prognosis (HR = 2.7, CI 1.4-5.1, p = 0.003 and HR = 2.8, CI 1.4-5.5, p = 0.004, respectively) compared to those with intermediate levels. CONCLUSIONS: Our findings suggest that the association between any of the three HER2 biomarkers and RFS was nonlinear. Patients with tumors with the highest levels of HER2 gene amplification or ERBB2 mRNA were associated with a worse prognosis than those with intermediate levels, which is of importance to investigate in future clinical trials studying HER2-targeted therapy.

Impact of Primary Breast Surgery on Overall Survival of Patients With De Novo Metastatic Breast Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Breast surgery in cases of de novo metastatic breast cancer (MBC) is associated with improved outcomes in retrospective studies, although the results of randomized controlled trials (RCTs) are conflicting. We aimed to investigate whether surgery in this context prolongs patient survival. METHODS: We performed a systematic review of the literature to identify RCTs comparing surgery of primary breast cancer to no surgery in patients with de novo MBC. Cochrane Library, Embase, Medline (OVID), and Web of Science were searched with latest update in July 2023, while conference proceedings were manually searched. Data concerning patient and tumor characteristics, as well as outcomes, were extracted. A meta-analysis with random effects models was performed considering heterogeneity between trials. RESULTS: Overall, 3255 entries were identified and 5 RCTs fulfilled all inclusion criteria, which had enrolled 1381 patients. The overall estimation in the intention-to-treat population showed no benefit for patients who had surgical excision of the primary breast tumor (HR = 0.93; 95% CI, 0.76-1.14). No subgroups in terms of receptor status or patterns of metastasis seemed to benefit from surgery, except for younger/premenopausal patients (HR = 0.74, 95% CI, 0.58-0.94). Breast surgery was associated with improved local progression-free survival (HR = 0.37, 95% CI, 0.19-0.74). CONCLUSION: Surgery of the primary tumor in patients with de novo MBC does not prolong survival, except possibly in younger/premenopausal patients. Breast surgery should be offered within the context of well-designed clinical trials examining the issue.

Treatment utilization and effectiveness of neoadjuvant chemotherapy comparing men and women diagnosed with breast cancer: a Swedish retrospective cohort study.

PURPOSE: Evidence supporting the use of neoadjuvant chemotherapy (NAC) in early breast cancer is based on studies mainly including women, whereas the utilization and effectiveness of NAC in men is less studied. The present study aimed to investigate the utilization and effectiveness of NAC in men and women with early breast cancer. METHODS: Eligible patients were identified through the Swedish National Breast Cancer Quality Register, that includes all newly diagnosed breast cancer cases in Sweden from 2008 and onwards. For the treatment utilization analysis, all patients with stage I-III between 2008 and 2020 were included (n = 82,888), whereas for the effectiveness analysis the cohort was restricted to patients receiving NAC (n = 6487). For both analyses, multivariate logistic regression models were applied to investigate potential sex disparities in NAC utilization and effectiveness, adjusted for patient- and tumor characteristics. RESULTS: In the NAC utilization analysis, 487 men and 82,401 women with stage I-III were included. No statistically significant difference between sexes in terms of NAC utilization was observed (adjusted Odds Ratio (adjOR): 1.135; 95% Confidence Interval (CI) 0.606-2.128) with an overall utilization rate of 4.9% in men compared to 7.8% in women. Among the 24 men and 6463 women who received NAC, the pathologic complete response (pCR) rates were 16.7% and 21.2%, respectively (adjOR: 1.141; 95% CI 0.141-9.238). CONCLUSION: The present study did not find any sex disparities in NAC utilization or effectiveness in terms of pCR. This supports the current recommendations of treating men with breast cancer with the same indications for NAC as women.

Risk factors for the increasing incidence of pregnancy-associated cancer in Sweden - a population-based study.

INTRODUCTION: The incidence of cancer during pregnancy and within first year post-delivery, ie pregnancy-associated cancer (PAC), is increasing in many countries, but little is known about risk factors for these trends. This study quantified incidence of PAC by trimesters and post-delivery periods, and assessed the role of maternal age, parity, immigrant status, education, smoking and body mass index for the risk and incidence trends of PAC. MATERIAL AND METHODS: We used data from the national birth and cancer registers in Sweden during 1973-2017 to define a register-based cohort of women aged 15-44 years. Incidence rates of PAC during pregnancy and up to 1 year post-delivery were calculated per 100 000 deliveries per year. Poisson regression with multiple imputation estimated incidence rate ratios with 95% confidence intervals adjusted by year, age, previous parity, immigrant status, education, smoking and BMI during 1990-2017, when information on risk factors was available. RESULTS: Among 4 557 284 deliveries, a total of 1274 (during pregnancy) and 3355 (within 1 year post-delivery) cases of PAC were diagnosed, with around 50 cases/year diagnosed during pregnancy and 110 cases/year during the first year post-delivery in the latest period 2015-2017. The most common cancer types during pregnancy were malignant melanoma, breast and cervical cancer, together accounting for 57% of cases during pregnancy and 53% during the first year post-delivery. The numbers of PAC were lower during pregnancy than during post-delivery for all tumor types with lowest numbers during first trimester. The PAC incidence rates increased over calendar time. High maternal age at diagnosis, smoking, nulliparity and non-immigrant background were associated with significantly higher risks of PAC. The increasing PAC incidence was in part explained by higher maternal age over time, but not by the other factors. CONCLUSIONS: High maternal age is the strongest risk factor for PAC. We show for the first time that smoking, nulliparity and non-immigrant background are also contributing risk factors for PAC. However, only high maternal age contributed significantly to the increasing incidence. Further studies on other potential risk factors for PAC are warranted, since our results indicate that age on its own does not fully explain the increase.

De novo metastatic breast cancer in men vs women: a Swedish population-based cohort study.

Current evidence on de novo metastatic breast cancer is based on data from women. This Swedish population-based cohort study compared the incidence over time and prognosis of de novo metastatic breast cancer between sexes using data from the Swedish National Quality Register for Breast Cancer. Joinpoint regression analysis was used to compare incidence trends in all stages (104 733 women, 648 men) and multivariate Cox regression analysis to investigate potential sex disparities in de novo metastatic breast cancer prognosis (6005 women, 41 men). For both sexes, increased trends were evident for cancer stages I and II, with a stabilizing trend at the later years for women, while stage III incidence remained stable. An increased trend for de novo metastatic breast cancer in women, and to a lesser extent in men, was observed. No difference in de novo metastatic breast cancer overall survival between sexes was observed (hazard ratio = 1.24; 95% confidence interval = 0.85 to 1.81). The comparable features in terms of incidence and prognosis of de novo metastatic breast cancer between sexes imply similarities, supporting the adoption of common treatment strategies.

Risk-adjusted benchmarking of long-term overall survival in patients with HER2-positive early-stage Breast cancer: A Swedish retrospective cohort study.

AIM: The main objective of the current study was to explore the value of risk-adjustment when comparing (i.e. benchmarking) long-term overall survival (OS) in breast cancer (BC) between Swedish regions. We performed risk-adjusted benchmarking of 5- and 10-year OS after HER2-positive early BC diagnosis between Sweden's two largest healthcare regions, constituting approximately a third of the total population in Sweden. METHODS: All patients diagnosed with HER2-positive early-stage BC between 01-01-2009 and 31-12-2016 in healthcare regions Stockholm-Gotland and Skane were included in the study. Cox proportional hazards model was used for risk-adjustment. Unadjusted (i.e. crude) and adjusted 5- and 10-year OS was benchmarked between the two regions. RESULTS: The crude 5-year OS was 90.3% in the Stockholm-Gotland region and 87.8% in the Skane region. The crude 10-year OS was 81.7% in the Stockholm-Gotland region and 77.3% in the Skane region. However, when adjusted for age, menopausal status and tumour biology, there was no significant OS disparity between the regions, neither at the 5-year nor 10-year follow-up. CONCLUSION: This study showed that risk-adjustment is relevant when benchmarking OS in BC, even when comparing regions from the same country that share the same national treatment guidelines. This is, to our knowledge, the first published risk-adjusted benchmarking of OS in HER2-positive BC.

Risk of obstetric and perinatal complications in women presenting with breast cancer during pregnancy and the first year postpartum in Sweden 1973-2017: A population-based matched study.

INTRODUCTION: For women presenting with breast cancer during pregnancy, treatment guidelines were historically restricted to only surgical treatment. Over the past decades, chemotherapy administered during pregnancy has been gradually introduced. Although breast cancer treatments during ongoing pregnancy have been deemed safe, detailed information on potential obstetric risks is lacking. We aimed to assess the risk of adverse obstetric and perinatal outcomes of breast cancer in pregnancy and within 1 year postpartum and in relation to trimester at breast cancer diagnosis, tumor stage, and cancer treatment during pregnancy. MATERIAL AND METHODS: Population-based matched study. Women diagnosed with breast cancer during pregnancy in 1973-2017 were identified in the Swedish Cancer Register and the Medical Birth Register, with additional information from the National Quality Register for Breast Cancer. Each birth with maternal breast cancer (n = 208 pregnant, n = 672 postpartum) was matched by age, calendar year, and birth order to 10 unexposed births from cancer-free women in the population (n = 2080 and n = 6720). Adjusted conditional logistic and multinomial regression models were used to estimate odds ratios and relative risk ratios, commonly denoted relative risks (RR) with 95% confidence intervals (CI), of adverse obstetric and perinatal outcomes. RESULTS: Breast cancer during pregnancy was associated with higher risks of preterm birth, both planned (RR 67.1, 95% CI 33.2-135.6) and spontaneous preterm birth (RR 3.8, 95% CI 2.0-7.5), and low birthweight (<2500 g: RR 7.5, 95% CI 4.9-11.3). The associated risks were higher if the breast cancer was diagnosed in the second trimester, and of similar magnitude irrespective of stage and treatment groups. There was a higher risk of low birthweight for gestational age (<25th centile) if breast cancer was diagnosed in the first trimester (RR 2.8, 95% CI 1.1-7.3). Risks of other pregnancy complications were similar to those of unexposed women, as were risks of neonatal mortality and malformations. Postpartum breast cancer was only associated with bleeding during pregnancy (RR 1.6, 95% CI 1.0-2.8). CONCLUSIONS: Preterm birth and related adverse outcomes were more common in women diagnosed with breast cancer during pregnancy. Reassuringly, breast cancer was not associated with other maternal pregnancy complications or adverse outcomes in children.

OptiBra study, a randomized controlled trial on optimal postoperative bra support after breast cancer surgery.

AIM: This randomized controlled trial aimed to compare two different postoperative bras after breast cancer surgery and evaluate their impact on primary outcome pain. METHOD: The study included 201 patients scheduled for primary surgery (breast conserving surgery with sentinel node biopsy or axillary clearance, mastectomy, or mastectomy with primary implant reconstruction with sentinel node biopsy or axillary clearance). Participants were randomized to either a soft bra or stable bra with compression. The patients were recommended to use the bra 24 h/day for 3 weeks, record daily pain (NRS), analgesic use and hours of bra use. RESULTS: Follow up was completed by 184 patients. No significant differences between the arms were found considering pain score over time, neither day 1-14, nor after 3 weeks. Sixty-eight percent of all patients, regardless of randomization, reported pain during the first 14 days. After 3 weeks 46% still reported pain in the operated breast. Among these, patients randomized to the stable bra with compression reported significantly lower pain score than those randomized to the soft bra. Patients who used the stable bra with compression reported significantly higher levels of comfort, sense of security during activity, less difficulty moving the arm, as well as support and stability for the operated breast compared to those using the soft bra. CONCLUSION: Using a stable bra with compression is the optimal evidence-based choice after breast cancer surgery to reduce remaining pain 3 weeks after surgery, increasing mobility, comfort, and sense of security. TRIAL REGISTRATION NUMBER: NCT04059835 at www. CLINICALTRIALS: gov.

Proteogenomics decodes the evolution of human ipsilateral breast cancer.

Ipsilateral breast tumor recurrence (IBTR) is a clinically important event, where an isolated in-breast recurrence is a potentially curable event but associated with an increased risk of distant metastasis and breast cancer death. It remains unclear if IBTRs are associated with molecular changes that can be explored as a resource for precision medicine strategies. Here, we employed proteogenomics to analyze a cohort of 27 primary breast cancers and their matched IBTRs to define proteogenomic determinants of molecular tumor evolution. Our analyses revealed a relationship between hormonal receptors status and proliferation levels resulting in the gain of somatic mutations and copy number. This in turn re-programmed the transcriptome and proteome towards a highly replicating and genomically unstable IBTRs, possibly enhanced by APOBEC3B. In order to investigate the origins of IBTRs, a second analysis that included primaries with no recurrence pinpointed proliferation and immune infiltration as predictive of IBTR. In conclusion, our study shows that breast tumors evolve into different IBTRs depending on hormonal status and proliferation and that immune cell infiltration and Ki-67 are significantly elevated in primary tumors that develop IBTR. These results can serve as a starting point to explore markers to predict IBTR formation and stratify patients for adjuvant therapy.

The Natural History of Ductal Carcinoma In Situ of the Breast - An Overview.

Ductal carcinoma in situ (DCIS) of the breast is a heterogenous disease and its natural history cannot be directly observed as surgical removal is part of the current standard of care. Studies of incompletely excised breast lesions that were considered benign after biopsy, but at review years later were recognized as DCIS, offers some insight to the natural history of DCIS. Summarizing these retrospective data; 14-53 % of the cases retrospectively diagnosed as DCIS progressed to invasive breast cancer (IBC) during follow-up. While observations from retrospective re-evaluation of biopsies and autopsies adds epidemiological input for understanding the natural history of DCIS, the most important results are still awaited from the ongoing prospective studies on active surveillance of DCIS. These studies with collected data on patient characteristics, life-style and environmental factors, as well as tumor and stromal metabolomics and genomics, will probably further elucidate the natural history of DCIS and how the disease should be treated in the future.

Local Recurrence after Treatment of Ductal Carcinoma In Situ: A Comprehensive Overview.

Patients with DCIS have an excellent long-term prognosis with a 10-year breast cancer-specific survival around 98%. Treatment has the goal to prevent the development of an invasive breast cancer and to minimize the risk for a second breast cancer event, and published studies have shown a substantial decrease in invasive local recurrence rates over time. Approximately 50% of the local recurrences after BCS for a primary DCIS are invasive and 8.5% of them node-positive. Experiencing an ipsilateral invasive recurrence after a primary DCIS does significantly increase the risk of breast cancer death, while this is not seen after a DCIS recurrence. Radical surgery remains crucial to minimize the risk of local recurrence, and adjuvant radiotherapy reduces the risk of local recurrence by at least 50%. At recurrence, a repeat-BCS should be considered as it offers a good local control in properly selected patients and an overall and breast cancer-specific survival comparable to that seen after mastectomy.

Cancer survival in women diagnosed with pregnancy-associated cancer: An overview using nationwide registry data in Sweden 1970-2018.

BACKGROUND: Pregnancy-associated cancer (PAC) is increasing over time in many countries. We provide a comprehensive, population-based overview of cancer survival in women with PAC across five decades. METHODS: We performed a nationwide cohort study of 121,382 women diagnosed with cancer at age 15-49 between 1970 and 2018 using birth and cancer registers in Sweden. Pregnancy-associated cancer was defined as diagnosed during pregnancy and within one year of delivery, while non-PAC was outside this window. Cox regression estimated adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) comparing cancer mortality for PAC versus non-PAC. RESULTS: In total, 5079 women had a diagnosis of PAC. Cutaneous malignant melanoma, breast, cervical, thyroid and central nervous system (CNS) were the most common sites of PAC. A higher cancer mortality was observed in PAC versus non-PAC for breast (HR = 1.72, 95% CI 1.54-1.93) and uterine cancer (myometrium/unspecified) (8.62, 2.80-26.53), in which all PAC deaths were uterine sarcomas. Increased mortality was also observed in upper digestive tract cancer diagnosed during pregnancy and colon cancer diagnosed during first year after delivery. Contrary, the HR for CNS tumours was significantly decreased (0.71, 0.55-0.91). Survival after PAC improved for most sites over time, with survival after breast cancer during pregnancy in recent years being similar to that of non-pregnancy associated breast cancer. CONCLUSION: For the majority of sites, PAC was not associated with poorer prognosis compared to non-PAC, a finding which was stable over time. The main exceptions were breast cancer and rarer cancers, such as uterine sarcoma.

Aromatase inhibitors use and risk for cardiovascular disease in breast cancer patients: A population-based cohort study.

BACKGROUND: Prior studies regarding use of Aromatase inhibitors (AIs) and risk for cardiovascular disease (CVD) have shown conflicting results. This retrospective cohort study aimed to investigate whether AIs use affects risk for CVD events in postmenopausal breast cancer survivors. METHODS: Using a retrospective cohort study design, four CVD outcomes; heart failure or cardiomyopathy, arrhythmia, acute ischemic heart disease and ischemic stroke or Transient Ischemic Attack were compared with uni- and multivariate Cox regression analyses according to exposure to endocrine therapy (use of AI, tamoxifen or AI/tamoxifen sequentially) or no endocrine therapy. RESULTS: In total 15815 postmenopausal women, surgically treated to early breast cancer during 2006-2012, were included. No significantly increased risk for CVD events was observed in patients with AI use in the whole cohort. However, two subgroup analyses showed increased risk for CVD events in the AI/tamoxifen sequential group; heart failure in patients older than 75 years (Hazard Ratio (HR) 2.44; 95% Confidence Interval (CI): 1.32-4.54) and arrhythmia in patients without prior CVD (HR 1.45; 95% CI: 1.01-2.10). An increased risk for arrhythmia and acute ischemic heart disease in patients with at least four years of AI treatment compared with no or short-time exposure was observed (HR 2.12; 95% CI: 1.40-3.25 for arrhythmia; HR 2.03; 95% CI: 1.15-3.58 for ischemic heart disease). CONCLUSION: Our results indicate an increased risk for ischemic heart disease and arrhythmia in patients treated for more than four years with AIs. This should be considered in the risk-benefit assessment concerning endocrine therapy.

Risk of primary lung cancer after adjuvant radiotherapy in breast cancer-a large population-based study.

Adjuvant radiotherapy (RT) for breast cancer (BC) has been associated with an increased risk of later radiation-induced lung cancer (LC). We examined the risk of primary LC in a population-based cohort of 52300 women treated for BC during 1992 to 2012, and 253796 age-matched women without BC. Cumulative incidence of LC was calculated by the Kaplan-Meier method, and the risk of LC after BC treatment was estimated by Cox proportional hazards regression analyses. Women with BC receiving RT had a higher cumulative incidence of LC compared to women with BC not receiving RT and women without BC. This became apparent 5 years after RT and increased with longer follow-up. Women with BC receiving RT had a Hazard ratio of 1.59 (95% confidence interval 1.37-1.84) for LC compared to women without BC. RT techniques that lower the incidental lung doses, e.g breathing adaption techniques, may lower this risk.

An Aggregated Comorbidity Measure Based on History of Filled Drug Prescriptions: Development and Evaluation in Two Separate Cohorts.

BACKGROUND: The ability to account for comorbidity when estimating survival in a population diagnosed with cancer could be improved by using a drug comorbidity index based on filled drug prescriptions. METHODS: We created a drug comorbidity index from age-stratified univariable associations between filled drug prescriptions and time to death in 326,450 control males randomly selected from the general population to men with prostate cancer. We also evaluated the index in 272,214 control females randomly selected from the general population to women with breast cancer. RESULTS: The new drug comorbidity index predicted survival better than the Charlson Comorbidity Index (CCI) and a previously published prescription index during 11 years of follow-up. The concordance (C)-index for the new index was 0.73 in male and 0.76 in the female population, as compared with a C-index of 0.67 in men and 0.69 in women for the CCI. In men of age 75-84 years with CCI = 0, the median survival time was 7.1 years (95% confidence interval [CI] = 7.0, 7.3) in the highest index quartile. Comparing the highest to the lowest drug comorbidity index quartile resulted in a hazard ratio (HR) of 2.2 among men (95% CI = 2.1, 2.3) and 2.4 among women (95% CI = 2.3, 2.6). CONCLUSIONS: A new drug comorbidity index based on filled drug prescriptions improved prediction of survival beyond age and the CCI alone. The index will allow a more accurate baseline estimation of expected survival for comparing treatment outcomes and evaluating treatment guidelines in populations of people with cancer.

Variability in Breast Cancer Biomarker Assessment and the Effect on Oncological Treatment Decisions: A Nationwide 5-Year Population-Based Study.

We compared estrogen receptor (ER), progesterone receptor (PR), human epidermal growth-factor receptor 2 (HER2), Ki67, and grade scores among the pathology departments in Sweden. We investigated how ER and HER2 positivity rates affect the distribution of endocrine and HER2-targeted treatments among oncology departments. All breast cancer patients diagnosed between 2013 and 2018 in Sweden were identified in the National Quality Register for Breast Cancer. Cases with data on ER, PR, HER2, Ki67, grade, and treatment were selected (43,261 cases from 29 departments following the guidelines for biomarker testing). The ER positivity rates ranged from 84.2% to 97.6% with 6/29 labs out of the overall confidence intervals (CIs), while PR rates varied between 64.8% and 86.6% with 7/29 labs out of the CIs. HER2 positivity rates ranged from 9.4% to 16.3%, with 3/29 labs out of the overall CIs. Median Ki67 varied between 15% and 30%, where 19/29 labs showed significant intra-laboratory variability. The proportion of grade-II cases varied between 42.9% and 57.1%, and 13/29 labs were outside of the CI. Adjusting for patient characteristics, the proportion of endocrine and anti-HER2 treatments followed the rate of ER and HER2 positivity, illustrating the clinical effect of inter- and intra-laboratory variability. There was limited variability among departments in ER, PR, and HER2 testing. However, even a few outlier pathology labs affected endocrine and HER2-targeted treatment rates in a clinically relevant proportion, suggesting the need for improvement. High variability was found in grading and Ki67 assessment, illustrating the need for the adoption of new technologies in practice.

In modern times, how important are breast cancer stage, grade and receptor subtype for survival: a population-based cohort study.

BACKGROUND: In breast cancer, immunohistochemistry (IHC) subtypes, together with grade and stage, are well-known independent predictors of breast cancer death. Given the immense changes in breast cancer treatment and survival over time, we used recent population-based data to test the combined influence of IHC subtypes, grade and stage on breast cancer death. METHODS: We identified 24,137 women with invasive breast cancer aged 20 to 74 between 2005 and 2015 in the database of the Cancer Registry of Norway. Kaplan-Meier curves, mortality rates and adjusted hazard ratios for breast cancer death were estimated by IHC subtypes, grade, tumour size and nodal status during 13 years of follow-up. RESULTS: Within all IHC subtypes, grade, tumour size and nodal status were independent predictors of breast cancer death. When combining all prognostic factors, the risk of death was 20- to 40-fold higher in the worst groups compared to the group with the smallest size, low grade and ER+PR+HER2- status. Among node-negative ER+HER2- tumours, larger size conferred a significantly increased breast cancer mortality. ER+PR-HER2- tumours of high grade and advanced stage showed particularly high breast cancer mortality similar to TNBC. When examining early versus late mortality, grade, size and nodal status explained most of the late (> 5 years) mortality among ER+ subtypes. CONCLUSIONS: There is a wide range of risks of dying from breast cancer, also across small breast tumours of low/intermediate grade, and among node-negative tumours. Thus, even with modern breast cancer treatment, stage, grade and molecular subtype (reflected by IHC subtypes) matter for prognosis.

Long-Term Prognostication for 20 114 Women With Small and Node-Negative Breast Cancer (T1abN0).

Background: Although small, node-negative breast cancer (ie, T1abN0) constitutes 20% of all newly diagnosed breast cancers, data on prognosis and prognostic factors are limited. Methods: We conducted a population-based cohort study including 20 114 Swedish women treated for T1abN0 breast cancer from 1977 onward. Patient and tumor data were collected from Swedish breast cancer registries. Cohort subjects were followed through linkage to the Cause of Death Register. We calculated the cumulative incidence of breast cancer-specific and overall death and used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: During a median follow-up of 9.1 years (range = 0-38), 915 women died of breast cancer and 5416 of any cause. The 10-, 20-, and 30-year cumulative incidences of breast cancer death were 3.4% (95% CI = 3.1% to 3.7%), 7.6% (95% CI = 7.1% to 8.2%), and 10.5% (95% CI = 9.6% to 11.4%), respectively. The multivariable hazard ratios and 95% confidence intervals of breast cancer death were 0.92 (95% CI = 0.88 to 0.97) for each additional calendar year of diagnosis, 4.38 (95% CI = 2.79 to 6.87) for grade 3 vs grade 1 tumors, 0.43 (95% CI = 0.31 to 0.62) for progesterone receptor-positive vs progesterone receptor-negative disease, and 2.01 (95% CI = 0.99 to 4.07) for HER2-positive vs HER2-negative disease. Women with grade 3 vs grade 1 tumors had a 56% increased risk of death from any cause (HR = 1.56, 95% CI = 1.30 to 1.88). Conclusions: The risk of breast cancer death in T1abN0 disease continues to increase steadily beyond 10 years after diagnosis, has improved over time, and varies substantially by tumor characteristics.