Survival following adjuvant trastuzumab-based treatment among older patients with HER2-positive early invasive breast cancer: A national population-based cohort study using routine data.

BACKGROUND: Randomised controlled trials (RCTs) reported adjuvant trastuzumab-based treatment improved overall survival (OS) among patients with HER2-positive early invasive breast cancer (EIBC). Few RCTs included older patients or those with comorbidity/frailty. This study aimed to determine whether the effect of adjuvant trastuzumab-based treatment on survival outcomes varies by patient age and fitness, using national data from routine care. METHODS: Women (50+ years) newly-diagnosed with HER2-positive EIBC between 2014 and 2019 were identified from England Cancer Registry data. Registration records were linked to Systemic Anti-Cancer Therapy data for treatment details and ONS death register for mortality details. A propensity score analysis employing the inverse probability of treatment weighting method was used to balance the patient variables across treatment groups. Cox models were used to evaluate whether the effect of treatment on OS was associated with patient age and fitness; competing risks regression models were used for breast cancer-specific survival (BCSS). RESULTS: 5238 women initiated adjuvant trastuzumab-based treatment. Median follow-up was 56.7 months. Comparison with 3421 women who did not receive adjuvant trastuzumab highlighted differences at diagnosis in relation to age, fitness, grade, nodal involvement, surgery type and use of radiotherapy. Weighted survival analysis found trastuzumab was associated with improved OS (hazard ratio HR 0.56, 95 %CI: 0.45-0.70) and improved BCSS (subHR 0.62, 95 %CI: 0.47-0.82). We found no evidence of a difference in effect by age or patient fitness for either outcome. CONCLUSION: In this national dataset, adjuvant trastuzumab was associated with improvements in survival, with an OS effect size similar to RCT evidence. The effect size was not found to vary by patient age or fitness. Chronological age and fitness alone should not be barriers to receipt of effective adjuvant targeted treatment.

Locoregional recurrence in studies of primary systemic therapy in early invasive breast cancer.

INTRODUCTION: The use of primary systemic therapy (PST) in early invasive breast cancer is routine but there are concerns about risk of locoregional recurrence. METHODS: We conducted a systematic literature review to identify studies of locoregional treatment and recurrence in patients with early invasive breast cancer who received non-endocrine PST. RESULTS: We identified 112 studies (18 prospective trials and 94 non-interventional studies). The use of surgery and radiotherapy after PST was recorded in 65 (58 %) and 50 (45 %) of studies respectively. 66 (59 %) studies reported locoregional recurrence. Cumulative 5-year locoregional recurrence risks varied from 1 % to 23 %. Locoregional recurrence was higher in patients under the age of 40, those who did not achieve a pathological complete remission after PST, had ER-negative or HER2 negative tumours, were recorded to have inoperable disease before PST, and did not have radiotherapy. LRR rates in these studies have not fallen over the overall calendar period of patient enrollment (1999-2016). CONCLUSION: The recording of locoregional treatments and outcomes is suboptimal in studies of PST and efforts to improve this are required. In the absence of randomised evidence, our findings may help to inform care and guideline development. We were unable to exclude concern that the use of PST is associated with a higher than desired risk of locoregional recurrence.

Exploring locoregional treatment reporting in neoadjuvant systemic breast cancer treatment studies: A systematic review.

Accurate information about locoregional treatments in breast cancer neoadjuvant systemic therapy (NST) trials is vital to support surgical decision-making and allow meaningful interpretation of long-term oncological outcomes. This systematic review (PROSPERO registration CRD42023470891) aimed to describe the current practice of outcome reporting in NST studies. A systematic search identified primary research studies published 01/01/2018-08/09/2023 reporting outcomes in patients receiving NST for breast cancer followed by locoregional treatment. Included were randomised controlled trials (RCTs) and non-randomised studies (NRS) with >250 participants reporting at least one locoregional treatment outcome. Outcomes were extracted verbatim and categorised using content analysis. Descriptive statistics were used to summarise results. Of the 3111 abstracts screened, 137 studies (22 RCTs and 115 NRS) reporting at least one locoregional outcome in 575,531 patients were included. The 137 studies reported a total of 510 surgical outcomes with a median of 3 (range 1-12) per study. No single outcome was reported in all studies. Type of breast (n = 129, 94.2 %) and axillary (n = 86, 62.8 %) surgery were reported most frequently. Only 34 % (n = 47) studies reported how treatment response was assessed and if/how this informed surgical decision-making. Only a fifth (n = 28) reported outcomes relating to surgical de-escalation. Only 72 studies (52.6 %) reported any radiation therapy (RT)-related outcome, most frequently whether RT had been received (n = 63/72, 87.5 %). Current reporting of locoregional treatment outcomes in NST studies is poor, inconsistent and urgently needs to be improved. A core outcome set and reporting guidelines may improve the quality and value of future research.

Survival outcomes after breast cancer surgery among older women with early invasive breast cancer in England: population-based cohort study.

BACKGROUND: This study assessed the influence of age, co-morbidity and frailty on 5-year survival outcomes after breast conservation surgery (BCS) with radiotherapy (RT) versus mastectomy (with or without RT) in women with early invasive breast cancer. METHODS: Women aged over 50 years with early invasive breast cancer diagnosed in England (2014-2019) who had breast surgery were identified from Cancer Registry data. Survival estimates were calculated from a flexible parametric survival model. A competing risk approach was used for breast cancer-specific survival (BCSS). Standardized survival probabilities and cumulative incidence functions for breast cancer death were calculated for each treatment by age. RESULTS: Among 101 654 women, 72.2% received BCS + RT and 27.8% received mastectomy. Age, co-morbidity and frailty were associated with overall survival (OS), but only age and co-morbidity were associated with BCSS. Survival probabilities for OS were greater for BCS + RT (90.3%) versus mastectomy (87.0%), and the difference between treatments varied by age (50 years: 1.9% versus 80 years: 6.5%). Cumulative incidence functions for breast cancer death were higher after mastectomy (5.1%) versus BCS + RT (3.9%), but there was little change in the difference by age (50 years: 0.9% versus 80 years: 1.2%). The results highlight the change in baseline mortality risk by age for OS compared to the stable baseline for BCSS. CONCLUSION: For OS, the difference in survival probabilities for BCS + RT and mastectomy increased slightly with age. The difference in cumulative incidence functions for breast cancer death by surgery type was small regardless of age. Evidence on real-world survival outcomes among older populations with breast cancer is informative for treatment decision-making.

Protocol for the development of a core outcome set and reporting guidelines for locoregional treatment in neoadjuvant systemic breast cancer treatment trials: the PRECEDENT project.

INTRODUCTION: Neoadjuvant systemic anticancer therapy (neoSACT) is increasingly used in the treatment of early breast cancer. Response to therapy is prognostic and allows locoregional and adjuvant systemic treatments to be tailored to minimise morbidity and optimise oncological outcomes and quality of life. Accurate information about locoregional treatments following neoSACT is vital to allow the translation of downstaging benefits into practice and facilitate meaningful interpretation of oncological outcomes, particularly locoregional recurrence. Reporting of locoregional treatments in neoSACT studies, however, is currently poor. The development of a core outcome set (COS) and reporting guidelines is one strategy by which this may be improved. METHODS AND ANALYSIS: A COS for reporting locoregional treatment (surgery and radiotherapy) in neoSACT trials will be developed in accordance with Core Outcome Measures in Effectiveness Trials (COMET) and Core Outcome Set-Standards for Development guidelines. Reporting guidance will be developed concurrently.The project will have three phases: (1) generation of a long list of relevant outcome domains and reporting items from a systematic review of published neoSACT studies and interviews with key stakeholders. Identified items and domains will be categorised and formatted into Delphi consensus questionnaire items. (2) At least two rounds of an international online Delphi survey in which at least 250 key stakeholders (surgeons/oncologists/radiologists/pathologists/trialists/methodologists) will score the importance of reporting each outcome. (3) A consensus meeting with key stakeholders to discuss and agree the final COS and reporting guidance. ETHICS AND DISSEMINATION: Ethical approval for the consensus process will be obtained from the Queen's University Belfast Faculty Ethics Committee. The COS/reporting guidelines will be presented at international meetings and published in peer-reviewed journals. Dissemination materials will be produced in collaboration with our steering group and patient advocates so the results can be shared widely. REGISTRATION: The study has been prospectively registered on the COMET website (https://www.comet-initiative.org/Studies/Details/2854).

Prolonged bone health benefits for breast cancer patients following adjuvant bisphosphonate therapy: the BoHFAB study.

Adjuvant bisphosphonates are often recommended in postmenopausal women with early breast cancer at intermediate-to-high risk of disease recurrence, but the magnitude and duration of their effects on bone mineral density (BMD) and bone turnover markers (BTMs) are not well described. We evaluated the impact of adjuvant zoledronate on areal BMD and BTMs in a sub-group of patients who had completed the large 5-yr randomized Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial. About 224 women (recurrence free) who had completed the AZURE trial within the previous 3 mo were recruited from 20 UK AZURE trial sites. One hundred twenty had previously been randomized to zoledronate (19 doses of 4 mg over 5 yr) and 104 to the control arm. BMD and BTMs were assessed at sub-study entry, 6 (BTMs only), 12, 24, and 60 mo following the completion of AZURE. As expected, mean BMD, T-scores, and Z-scores at sub-study entry were higher in the zoledronate vs the control arm. At the lumbar spine, the mean (SD) standardized BMD (sBMD) was 1123 (201) and 985 (182) mg/cm2 in the zoledronate and control arms, respectively (P < .0001). The baseline differences in sBMD persisted at all assessed skeletal sites and throughout the 5-yr follow-up period. In patients completing zoledronate treatment, BTMs were significantly lower than those in the control arm (α- and ß-urinary C-telopeptide of type-I collagen, both P < .00001; serum intact pro-collagen I N-propeptide, P < .00001 and serum tartrate-resistant acid phosphatase 5b, P = .0001). Some offset of bone turnover inhibition occurred in the 12 mo following the completion of zoledronate treatment. Thereafter, during the 60 mo of follow-up, all BTMs remained suppressed in the zoledronate arm relative to the control arm. In conclusion, in addition to the known anti-cancer benefits of adjuvant zoledronate, there are likely to be positive, lasting benefits in BMD and bone turnover.

Invasive breast cancer and breast cancer death after non-screen detected ductal carcinoma in situ from 1990 to 2018 in England: population based cohort study.

OBJECTIVES: To evaluate the long term risks of invasive breast cancer and death related to breast cancer after non-screen detected ductal carcinoma in situ. Risks for women in the general population and for women diagnosed with ductal carcinoma in situ via the screening programme were compared. DESIGN: Population based cohort study. SETTING: Data from the National Disease Registration Service. PARTICIPANTS: All 27 543 women in England who were diagnosed with ductal carcinoma in situ, outside the NHS breast screening programme, during 1990 to 2018. MAIN OUTCOME MEASURES: Incident invasive breast cancer and death caused by breast cancer. RESULTS: By 31 December 2018, 3651 women with non-screen detected ductal carcinoma in situ had developed invasive breast cancer, more than four times higher than expected from national cancer incidence rates (ratio of observed to expected rate was 4.21 (95% conference interval 4.07 to 4.35)). The ratio of observed to expected rate of developing invasive breast cancer remained increased throughout follow-up among women aged <45-70 years. The 25 year cumulative risks of invasive breast cancer by age at diagnosis of ductal carcinoma in situ were 27.3% for <45 years, 25.2% for 45-49 years, 21.7% for 50-59 years, and 20.8% for 60-70 years. 908 women died of breast cancer, almost four times higher than that expected from breast cancer death rates in the general population (ratio of observed to expected rate 3.83 (3.59 to 4.09)). The ratio of observed to expected rate of mortality attributed to breast cancer remained increased throughout follow-up. The 25 year cumulative risks of breast cancer death by age at ductal carcinoma in situ diagnosis were 7.6% for <45 years, 5.8% for 45-49 years, 5.9% for 50-59 years, and 6.2% for 60-70 years. Among women aged 50-64 years, and therefore eligible for breast screening by the NHS, the ratio of observed to expected rate of invasive breast cancer in women with non-screen detected compared with screen detected ductal carcinoma in situ was 1.26 (95% conference interval 1.17 to 1.35), while the ratio for mortality from breast cancer was 1.37 (1.17 to 1.60). Among 22 753 women with unilateral ductal carcinoma in situ undergoing surgery, those who had mastectomy rather than breast conserving surgery had a lower 25 year cumulative rate of ipsilateral invasive breast cancer (mastectomy 8.2% (95% conference interval 7.0% to 9.4%), breast conserving surgery with radiotherapy 19.8% (16.2% to 23.4%), and breast conserving surgery with no radiotherapy recorded 20.6% (18.7% to 22.4%)). However, reductions did not translate into a lower 25 year cumulative rate of deaths attributable to breast cancer (mastectomy 6.5% (4.9% to 10.9%), breast conserving surgery with radiotherapy 8.6% (5.9% to 15.5%), breast conserving surgery with no radiotherapy recorded 7.8% (6.3% to 11.5%)). CONCLUSIONS: For at least 25 years after their diagnosis, women with non-screen detected ductal carcinoma in situ had higher long term risks of invasive breast cancer and breast cancer death than women in the general population. Additionally, they had higher long term risks than women with screen detected ductal carcinoma in situ. Mastectomy was associated with lower risks of invasive breast cancer than breast conserving surgery, even when accompanied by radiotherapy. However, risks of breast cancer death appeared similar for mastectomy, breast conserving surgery with radiotherapy, and breast conserving surgery with no radiotherapy recorded.

Mastectomy patterns among older women with early invasive breast cancer in England and Wales: A population-based cohort study.

INTRODUCTION: Older women with early invasive breast cancer (EIBC) are more likely to receive a mastectomy compared with younger women. This study assessed factors associated with receiving a mastectomy among older women with EIBC, with a particular focus on comorbidity and frailty. MATERIALS AND METHODS: Women diagnosed with EIBC (stages I-IIIa) aged ≥50 years from 2014 to 2019 in English and Welsh NHS organisations who received breast surgery were identified from cancer registration datasets linked to routine hospital data. Separate multivariable logistic regression models explored factors associated with mastectomy use, within each tumour stage (T1-T3). For each tumour stage, risk-adjusted rates of mastectomy were calculated for each NHS organisation and displayed using funnel plots. RESULTS: We included 106,952 women with EIBC: 23.4% received a mastectomy as their first breast cancer surgery. Receipt of mastectomy was more common among patients with a higher tumour stage (T1: 12.3%; T2: 37.6%; T3: 77.5%), and mastectomy use increased with age within each tumour stage category (50-59 vs 80 + years: 11.8% vs 26.3% for T1; 31.5% vs 56.9% for T2; 73.4% vs 90.3% for T3). Results from a multivariable regression model showed that more severe frailty was associated with mastectomy use for women with T1 (p = 0.002) or T2 (p = 0.003) tumours, but may not be for women with T3 tumours (p = 0.041). There was no association between comorbidity and mastectomy use after accounting for frailty (all p > 0.1). Adjusting for clinical and patient factors only slightly reduced the association between age and mastectomy use. Variation in mastectomy use between NHS organisations was greatest for women with T2 EIBC (unadjusted range: 17.7% to 68.4%). DISCUSSION: Older women with EIBC are more commonly treated with mastectomy. This could not be explained by tumour characteristics or physical fitness, raising questions about whether surgical decision-making inconsistently incorporates information on patient fitness and functional age.

Evidence into practice: a national cohort study of NICE-recommended oncological drug therapy utilisation among women diagnosed with invasive breast cancer in England.

BACKGROUND: Multiple drug treatments are approved for invasive breast cancer (IBC). We investigated uptake of NICE-recommended oncological drugs and variation by age, comorbidity burden and geographical region. METHODS: Women (aged 50+ years) diagnosed with IBC from 2014 to 2019, were identified from England Cancer Registry data and drug utilisation from Systemic Anti-Cancer Therapy data. Interrupted time series analysis assessed national-level changes in drug use after publication of NICE recommendations. Regression models analysed variation in use. RESULTS: This national cohort included 168,449 women. Use of drugs recommended for first-line treatment varied, from 26.6% for CDK 4/6 inhibitors to 63.8% for HER2-targeting therapies. Utilisation of drugs with a NICE recommendation published between 2014 and 2019, increased among patients diagnosed around the time of publication, except in the case of pertuzumab for metastatic breast cancer (MBC) which was previously accessible via the Cancer Drugs Fund (though use of pertuzumab for MBC increased from 34.1% to 75.0% across the study period). Use of trastuzumab and neoadjuvant/adjuvant pertuzumab varied by geographical region. Use was low for ribociclib (2.2%), abemaciclib (2.3%) and for drugs recommended beyond the first-line setting. For all drugs, use after NICE recommendation varied by age at diagnosis and increased as stage increased. CONCLUSIONS: Use of NICE-recommended drugs for IBC in routine care is variable, with lowest use among women aged 70+ years. Improving access to effective treatments is an important step in improving outcomes.

Predicting 10-year breast cancer mortality risk in the general female population in England: a model development and validation study.

BACKGROUND: Identifying female individuals at highest risk of developing life-threatening breast cancers could inform novel stratified early detection and prevention strategies to reduce breast cancer mortality, rather than only considering cancer incidence. We aimed to develop a prognostic model that accurately predicts the 10-year risk of breast cancer mortality in female individuals without breast cancer at baseline. METHODS: In this model development and validation study, we used an open cohort study from the QResearch primary care database, which was linked to secondary care and national cancer and mortality registers in England, UK. The data extracted were from female individuals aged 20-90 years without previous breast cancer or ductal carcinoma in situ who entered the cohort between Jan 1, 2000, and Dec 31, 2020. The primary outcome was breast cancer-related death, which was assessed in the full dataset. Cox proportional hazards, competing risks regression, XGBoost, and neural network modelling approaches were used to predict the risk of breast cancer death within 10 years using routinely collected health-care data. Death due to causes other than breast cancer was the competing risk. Internal-external validation was used to evaluate prognostic model performance (using Harrell's C, calibration slope, and calibration in the large), performance heterogeneity, and transportability. Internal-external validation involved dataset partitioning by time period and geographical region. Decision curve analysis was used to assess clinical utility. FINDINGS: We identified data for 11 626 969 female individuals, with 70 095 574 person-years of follow-up. There were 142 712 (1·2%) diagnoses of breast cancer, 24 043 (0·2%) breast cancer-related deaths, and 696 106 (6·0%) deaths from other causes. Meta-analysis pooled estimates of Harrell's C were highest for the competing risks model (0·932, 95% CI 0·917-0·946). The competing risks model was well calibrated overall (slope 1·011, 95% CI 0·978-1·044), and across different ethnic groups. Decision curve analysis suggested favourable clinical utility across all age groups. The XGBoost and neural network models had variable performance across age and ethnic groups. INTERPRETATION: A model that predicts the combined risk of developing and then dying from breast cancer at the population level could inform stratified screening or chemoprevention strategies. Further evaluation of the competing risks model should comprise effect and health economic assessment of model-informed strategies. FUNDING: Cancer Research UK.

Ki67 and breast cancer mortality in women with invasive breast cancer.

BACKGROUND: The percentage of cells staining positive for Ki67 is sometimes used for decision-making in patients with early invasive breast cancer (IBC). However, there is uncertainty regarding the most appropriate Ki67 cut points and the influence of interlaboratory measurement variability. We examined the relationship between breast cancer mortality and Ki67 both before and after accounting for interlaboratory variability and 8 patient and tumor characteristics. METHODS: A multicenter cohort study of women with early IBC diagnosed during 2009-2016 in more than 20 NHS hospitals in England and followed until December 31, 2020. RESULTS: Ki67 was strongly prognostic of breast cancer mortality in 8212 women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative early IBC (Ptrend < .001). This relationship remained strong after adjustment for patient and tumor characteristics (Ptrend < .001). Standardization for interlaboratory variability did little to alter these results. For women with Ki67 scores of 0%-5%, 6%-10%, 11%-19%, and 20%-29% the corresponding 8-year adjusted cumulative breast cancer mortality risks were 3.3% (95% confidence interval [CI] = 2.8% to 4.0%), 3.7% (95% CI = 3.0% to 4.4%), 3.4% (95% CI = 2.8% to 4.1%), and 3.4% (95% CI = 2.8% to 4.1%), whereas for women with Ki67 scores of 30%-39% and 40%-100%, these risks were higher, at 5.1% (95% CI = 4.3% to 6.2%) and 7.7% (95% CI = 6.6% to 9.1) (Ptrend < .001). Similar results were obtained when the adjusted analysis was repeated with omission of pathological information about tumor size and nodal involvement, which would not be available preoperatively for patients being considered for neoadjuvant therapy. CONCLUSION: Our findings confirm the prognostic value of Ki67 scores of 30% or more in women with ER-positive, HER2-negative early IBC, irrespective of interlaboratory variability. These results also suggest that Ki67 may be useful to aid decision-making in the neoadjuvant setting.

Completeness of endocrine therapy information in the Primary Care Prescription Database (PCPD) and secondary care treatment datasets: A national population-based cohort study using routine healthcare data.

BACKGROUND: Endocrine therapy (ET) is a widely used treatment for breast cancer. In the UK, use is typically initiated in secondary care, with subsequent treatment in primary care. Evaluating use of ET depends on data sources containing accurate and complete information. This study aimed to evaluate the completeness and consistency of ET recorded in primary and secondary care data (SCD) and determine the value of combining data sources in describing use of ET. METHODS: This cohort study included women (50 + years) diagnosed with hormone receptor-positive invasive breast cancer in England, April-2015 to December-2019. Concordance of ET recorded in SCD and the Primary Care Prescription Database (PCPD) was evaluated. Factors associated with recording of ET in each setting were assessed using statistical models. RESULTS: Overall 110,529 women were included. 94% had ET recorded in either SCD or PCPD. ET captured in SCD varied from 3% (in Systemic Anti-Cancer Therapy data) to 52% (in the Cancer Outcomes and Services Dataset; COSD). By contrast, 93% of patients had an ET prescription in PCPD. Among patients with ET recorded, this was not captured in COSD for 45%. Capture in COSD was lowest for younger women, those with no comorbidity/frailty, with lower stage or HER2-positive disease, or with other treatments recorded. Overall concordance between COSD and PCPD was 57%, but varied substantially across NHS trusts (lowest decile≤28%; highest decile≥86%). Among women with ET recorded in both settings, the earliest record was in COSD for 97%; 59% of initial ET prescriptions recorded in COSD were not captured in PCPD. Combining PCPD and COSD data enabled estimation of ET duration. CONCLUSIONS: PCPD is vital for understanding the use of ET within this population. Completeness of SCD could be improved by ensuring information on first ET prescription is recorded. PCPD (linked to SCD) is a valuable resource for examining patterns of care for patients with cancer, including treatment duration and adherence.

Patterns of chemotherapy use and outcomes in advanced non-small cell lung cancer by age in England: A retrospective analysis of the population-based Systemic Anti-Cancer Treatment (SACT) dataset.

INTRODUCTION: We described the patterns of chemotherapy use and outcomes in patients diagnosed with stage III or IV non-small cell lung cancer (NSCLC) by age in England. MATERIALS AND METHODS: In this retrospective population-based study, we included 20,716 (62% stage IV) patients with NSCLC diagnosed from 2014 to 2017 treated with chemotherapy. We used the Systemic Anti-Cancer Treatment (SACT) dataset to describe changes in treatment plan and estimated 30 and 90-day mortality rates and median, 6-, and 12-month overall survival (OS) using Kaplan Meier estimator for patients aged <75 and ≥ 75 by stage. Using flexible hazard regression models we assessed the impact of age, stage, treatment intent (stage III), and performance status on survival. RESULTS: Patients aged ≥75 years were less likely to receive two or more regimens, more likely to have their treatment modified because of comorbidities and their doses reduced compared to younger patients. However, early mortality rates and overall survival were similar across ages, apart from the oldest patients with stage III disease. DISCUSSION: This observational study demonstrates that age is associated with treatment patterns in an older population with advanced NSCLC in England. Although this reflects a pre-immunotherapy period, given the median age of NSCLC patients and increasingly older population, these results suggest older patients (>75 yrs) may benefit from more intense treatments.

Breast cancer mortality in 500 000 women with early invasive breast cancer diagnosed in England, 1993-2015: population based observational cohort study.

OBJECTIVES: To describe long term breast cancer mortality among women with a diagnosis of breast cancer in the past and estimate absolute breast cancer mortality risks for groups of patients with a recent diagnosis. DESIGN: Population based observational cohort study. SETTING: Routinely collected data from the National Cancer Registration and Analysis Service. PARTICIPANTS: All 512 447 women registered with early invasive breast cancer (involving only breast and possibly axillary nodes) in England during January 1993 to December 2015, with follow-up to December 2020. MAIN OUTCOME MEASURES: Annual breast cancer mortality rates and cumulative risks by time since diagnosis, calendar period of diagnosis, and nine characteristics of patients and tumours. RESULTS: For women with a diagnosis made within each of the calendar periods 1993-99, 2000-04, 2005-09, and 2010-15, the crude annual breast cancer mortality rate was highest during the five years after diagnosis and then declined. For any given time since diagnosis, crude annual breast cancer mortality rates and risks decreased with increasing calendar period. Crude five year breast cancer mortality risk was 14.4% (95% confidence interval 14.2% to 14.6%) for women with a diagnosis made during 1993-99 and 4.9% (4.8% to 5.0%) for women with a diagnosis made during 2010-15. Adjusted annual breast cancer mortality rates also decreased with increasing calendar period in nearly every patient group, by a factor of about three in oestrogen receptor positive disease and about two in oestrogen receptor negative disease. Considering just the women with a diagnosis made during 2010-15, cumulative five year breast cancer mortality risk varied substantially between women with different characteristics: it was <3% for 62.8% (96 085/153 006) of women but ≥20% for 4.6% (6962/153 006) of women. CONCLUSIONS: These five year breast cancer mortality risks for patients with a recent diagnosis may be used to estimate breast cancer mortality risks for patients today. The prognosis for women with early invasive breast cancer has improved substantially since the 1990s. Most can expect to become long term cancer survivors, although for a few the risk remains appreciable.

Development and internal-external validation of statistical and machine learning models for breast cancer prognostication: cohort study.

OBJECTIVE: To develop a clinically useful model that estimates the 10 year risk of breast cancer related mortality in women (self-reported female sex) with breast cancer of any stage, comparing results from regression and machine learning approaches. DESIGN: Population based cohort study. SETTING: QResearch primary care database in England, with individual level linkage to the national cancer registry, Hospital Episodes Statistics, and national mortality registers. PARTICIPANTS: 141 765 women aged 20 years and older with a diagnosis of invasive breast cancer between 1 January 2000 and 31 December 2020. MAIN OUTCOME MEASURES: Four model building strategies comprising two regression (Cox proportional hazards and competing risks regression) and two machine learning (XGBoost and an artificial neural network) approaches. Internal-external cross validation was used for model evaluation. Random effects meta-analysis that pooled estimates of discrimination and calibration metrics, calibration plots, and decision curve analysis were used to assess model performance, transportability, and clinical utility. RESULTS: During a median 4.16 years (interquartile range 1.76-8.26) of follow-up, 21 688 breast cancer related deaths and 11 454 deaths from other causes occurred. Restricting to 10 years maximum follow-up from breast cancer diagnosis, 20 367 breast cancer related deaths occurred during a total of 688 564.81 person years. The crude breast cancer mortality rate was 295.79 per 10 000 person years (95% confidence interval 291.75 to 299.88). Predictors varied for each regression model, but both Cox and competing risks models included age at diagnosis, body mass index, smoking status, route to diagnosis, hormone receptor status, cancer stage, and grade of breast cancer. The Cox model's random effects meta-analysis pooled estimate for Harrell's C index was the highest of any model at 0.858 (95% confidence interval 0.853 to 0.864, and 95% prediction interval 0.843 to 0.873). It appeared acceptably calibrated on calibration plots. The competing risks regression model had good discrimination: pooled Harrell's C index 0.849 (0.839 to 0.859, and 0.821 to 0.876, and evidence of systematic miscalibration on summary metrics was lacking. The machine learning models had acceptable discrimination overall (Harrell's C index: XGBoost 0.821 (0.813 to 0.828, and 0.805 to 0.837); neural network 0.847 (0.835 to 0.858, and 0.816 to 0.878)), but had more complex patterns of miscalibration and more variable regional and stage specific performance. Decision curve analysis suggested that the Cox and competing risks regression models tested may have higher clinical utility than the two machine learning approaches. CONCLUSION: In women with breast cancer of any stage, using the predictors available in this dataset, regression based methods had better and more consistent performance compared with machine learning approaches and may be worthy of further evaluation for potential clinical use, such as for stratified follow-up.

Proton Beam Therapy for Early Breast Cancer: A Systematic Review and Meta-analysis of Clinical Outcomes.

PURPOSE: Adjuvant proton beam therapy (PBT) is increasingly available to patients with breast cancer. It achieves better planned dose distributions than standard photon radiation therapy and therefore may reduce the risks. However, clinical evidence is lacking. METHODS AND MATERIALS: A systematic review of clinical outcomes from studies of adjuvant PBT for early breast cancer published in 2000 to 2022 was undertaken. Early breast cancer was defined as when all detected invasive cancer cells are in the breast or nearby lymph nodes and can be removed surgically. Adverse outcomes were summarized quantitatively, and the prevalence of the most common ones were estimated using meta-analysis. RESULTS: Thirty-two studies (1452 patients) reported clinical outcomes after adjuvant PBT for early breast cancer. Median follow-up ranged from 2 to 59 months. There were no published randomized trials comparing PBT with photon radiation therapy. Scattering PBT was delivered in 7 studies (258 patients) starting 2003 to 2015 and scanning PBT in 22 studies (1041 patients) starting 2000 to 2019. Two studies (123 patients) starting 2011 used both PBT types. For 1 study (30 patients), PBT type was unspecified. Adverse events were less severe after scanning than after scattering PBT. They also varied by clinical target. For partial breast PBT, 498 adverse events were reported (8 studies, 358 patients). None were categorized as severe after scanning PBT. For whole breast or chest wall ± regional lymph nodes PBT, 1344 adverse events were reported (19 studies, 933 patients). After scanning PBT, 4% (44/1026) of events were severe. The most prevalent severe outcome after scanning PBT was dermatitis, which occurred in 5.7% (95% confidence interval, 4.2-7.6) of patients. Other severe adverse outcomes included infection, pain, and pneumonitis (each ≤1%). Of the 141 reconstruction events reported (13 studies, 459 patients), the most prevalent after scanning PBT was prosthetic implant removal (34/181, 19%). CONCLUSIONS: This is a quantitative summary of all published clinical outcomes after adjuvant PBT for early breast cancer. Ongoing randomized trials will provide information on its longer-term safety compared with standard photon radiation therapy.

Concordance of cancer drug therapy information derived from routinely collected hospital admissions data and the Systemic Anti-Cancer Therapy (SACT) dataset, for older women diagnosed with early invasive breast cancer in England.

BACKGROUND: Evaluating uptake of oncological treatments, and subsequent outcomes, depends on data sources containing accurate and complete information about cancer drug therapy (CDT). This study aimed to evaluate the consistency of CDT information in the Hospital Episode Statistics Admitted Patient Care (HES-APC) and Systemic Anti-Cancer Therapy (SACT) datasets for early invasive breast cancer (EIBC). METHODS: The study included women (50 + years) diagnosed with EIBC in England from 2014 to 2019 who had surgery within six months of diagnosis. Concordance of CDT recorded in HES-APC (identified using OPCS codes) and SACT was evaluated at both patient-level and cycle-level. Factors associated with CDT use captured only in HES-APC were assessed using statistical models. RESULTS: The cohort contained 129,326 women with EIBC. Overall concordance between SACT and HES-APC on CDT use was 94 %. Concordance increased over the study period (91-96 %), and there was wide variation across NHS trusts (lowest decile of trusts had concordance≤77 %; highest decile≥99 %). Among women receiving CDT, 9 % (n = 2781/31693) of use was not captured in SACT; incompleteness was worst (18 %=47/259) among women aged 80 + and those diagnosed in 2014 (21%=1121/5401). OPCS codes in HES-APC were good at identifying patient-level and cycle-level use of trastuzumab or FEC chemotherapy (fluorouracil, epirubicin, cyclophosphamide), with 89 % and 93 % concordance with SACT respectively (patient-level agreement). Among cycles of solely oral CDT recorded in SACT, only 24 % were captured in HES-APC, compared to 71 % for intravenous/subcutaneous CDT. CONCLUSIONS: Combining information in HES-APC and SACT provides a more complete picture of CDT treatment in women aged 50 + receiving surgery for EIBC than using either data source alone. HES-APC may have particular value in identifying CDT use among older women, those diagnosed less recently, and in NHS trusts with low SACT data returns.