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In a meta-analysis of 88 trials involving nearly 63,000 women with breast cancer who were disease-free after 5 years of endocrine therapy, the risk of recurrence ranged from 10 to 41% between years 5 and 20, depending on nodal status and tumor grade.

A large study shows that irradiation of the chest in women with breast cancer delivers an average of about 5 Gy and that the risk of a subsequent coronary event increases at a rate of 7.4% per gray in a linear fashion, without a threshold and with no apparent decline over time. Randomized trials have shown that radiotherapy for early-stage breast cancer can reduce the rates of recurrence and of death from breast cancer. 1 , 2 However, long-term follow-up in some trials has shown that radiotherapy can also increase the risk of ischemic heart disease, presumably through incidental irradiation of the heart. 1 , 3 Radiotherapy regimens for breast cancer have changed since the women in these trials were irradiated, and the doses of radiation to which the heart is exposed are now generally lower. 4 Nevertheless, in most women, the heart still receives doses of 1 to 5 Gy. 5 – 11 Several studies have suggested that . . .

Radiotherapy for early breast cancer can decrease breast cancer mortality but increase other mortality, mainly from heart disease and lung cancer. The mean cardiac dose from irradiation of a left-sided breast cancer can be two or three times that for a right-sided breast cancer. The mean ipsilateral (ie, on the same side as the breast cancer) lung dose can also be two or three times the mean contralateral lung dose. Particularly during the 1970s, when typical heart and lung exposures were greater than now, the laterality of an irradiated breast cancer could measurably affect cardiac mortality and mortality from cancer of the right or the left lung decades later. This study aimed to assess the hazards in the general US population from routine cancer-registry and death-certificate data. We analysed data for 308 861 US women with early breast cancer of known laterality (left-sided or right-sided) who were registered in the US Surveillance Epidemiology and End Results (SEER) cancer registries during 1973–2001 and followed prospectively for cause-specific mortality until Jan 1, 2002. 115 165 (37%) received radiotherapy. Among those who did not, tumour laterality was of little relevance to subsequent mortality. For women diagnosed during 1973–82 and irradiated, the cardiac mortality ratio (left versus right tumour laterality) was 1·20 (95% CI 1·04–1·38) less than 10 years afterwards, 1·42 (1·11–1·82) 10–14 years afterwards, and 1·58 (1·29–1·95) after 15 years or more (trend: 2p=0·03). For women diagnosed during 1983–92 and irradiated, the cardiac mortality ratio was 1·04 (0·91–1·18) less than 10 years afterwards and 1·27 (0·99–1·63) 10 or more years afterwards. For women diagnosed during 1993–2001 and irradiated the cardiac mortality ratio was 0·96 (0·82–1·12), with none yet followed for 10 years. Among women irradiated for breast cancer who subsequently developed an ipsilateral or contralateral lung cancer, the lung cancer mortality ratio (ipsilateral versus contralateral) for women diagnosed during 1973–82 and irradiated was 1·17 (0·62–2·19), 2·00 (1·00–4·00), and 2·71 (1·65–4·48), respectively, less than 10 years, 10–14 years, and 15 or more years afterwards (trend: 2p=0·04). For women irradiated after 1982 there is, as yet, little information on lung cancer risks more than 10 years afterwards. US breast cancer radiotherapy regimens of the 1970s and early 1980s appreciably increased mortality from heart disease and lung cancer 10–20 years afterwards with, as yet, little direct evidence on the hazards after more than 20 years. Since the early 1980s, improvements in radiotherapy planning should have reduced such risks, but the long-term hazards in the general populations of various countries still need to be monitored directly.

Breast cancer can be categorised into a number of histological types, based on microscopic appearances. There is some evidence that the different breast cancer histological types are associated with different patient and tumour characteristics, but few previous studies have been large enough to investigate this systematically, especially for rare histological types. National cancer registration data were used to describe trends in the incidence of specific histological types of invasive breast cancer in women diagnosed when aged 18–89 years in England from January 1988 to December 2016, and to investigate associations between breast cancer histological types and patient and tumour characteristics. There were 838,776 women diagnosed with a first primary invasive breast cancer in this 29‐year period, including 614,698 (73%) cases of ductal carcinoma NST [no special type (NST)], 90,028 (11%) cases of lobular carcinoma, and more than 16,000 (2%) cases each of tubular and mucinous carcinomas. Rarer histological types included medullary, papillary, metaplastic, and cribriform carcinomas, with >1000 cases of each type. Data quality and completeness improved substantially during the study period. The different histological types of breast cancer showed different patterns in incidence by calendar period of diagnosis, age at diagnosis, and screen‐detection status, as well as different associations with tumour characteristics such as grade, stage at diagnosis, and molecular subtype. This large nationwide study provides an overview of the changing incidence of the different histological types of invasive breast cancer in England over almost 30 years. It also gives an opportunity to investigate the characteristics of rare histological types, which smaller studies have been unable to explore. In addition, the results demonstrate the continuing value of histological types defined by microscopic morphology, alongside newer molecular classifications.

McGale, P. and Darby, S. C. Low Doses of Ionizing Radiation and Circulatory Diseases: A Systematic Review of the Published Epidemiological Evidence. Radiat. Res. 163, 247– 257 (2005). Recent analyses of mortality among atomic bomb survivors have suggested a linear dose–response relationship between ionizing radiation and diseases of the circulatory system for exposures in the range 0–4 Sv. If confirmed, this has substantial implications. We have therefore reviewed the published literature to see if other epidemiological data support this finding. Other studies allowing a comparison of the rates of circulatory disease in individuals drawn from the same population but exposed to ionizing radiation at different levels within the range 0–5 Gy or 0–5 Sv were identified through systematic literature searches. Twenty-six studies were identified. In some, disease rates among those exposed at different levels may have differed for reasons unrelated to radiation exposure, while many had low power to detect effects of the relevant magnitude. Among the remainder, one study found appreciable evidence that exposure to low-dose radiation was associated with circulatory diseases, but five others, all with appreciable power, did not. We conclude that the other epidemiological data do not at present provide clear evidence of a risk of circulatory diseases at doses of ionizing radiation in the range 0–4 Sv, as suggested by the atomic bomb survivors. Further evidence is needed to characterize the possible risk.

For women with early-stage oestrogen receptor (ER)-positive breast cancer, adjuvant tamoxifen reduces 15-year breast cancer mortality by a third. Aromatase inhibitors are more effective than tamoxifen in postmenopausal women but are ineffective in premenopausal women when used without ovarian suppression. We aimed to investigate whether premenopausal women treated with ovarian suppression benefit from aromatase inhibitors. We did a meta-analysis of individual patient data from randomised trials comparing aromatase inhibitors (anastrozole, exemestane, or letrozole) versus tamoxifen for 3 or 5 years in premenopausal women with ER-positive breast cancer receiving ovarian suppression (goserelin or triptorelin) or ablation. We collected data on baseline characteristics, dates and sites of any breast cancer recurrence or second primary cancer, and dates and causes of death. Primary outcomes were breast cancer recurrence (distant, locoregional, or contralateral), breast cancer mortality, death without recurrence, and all-cause mortality. As distant recurrence invariably results in death from breast cancer several years after the occurrence, whereas locoregional recurrence and new contralateral breast cancer are not usually fatal, the distant recurrence analysis is shown separately. Standard intention-to-treat log-rank analyses estimated first-event rate ratios (RR) and their confidence intervals (CIs). We obtained data from all four identified trials (ABCSG XII, SOFT, TEXT, and HOBOE trials), which included 7030 women with ER-positive tumours enrolled between June 17, 1999, and Aug 4, 2015. Median follow-up was 8·0 years (IQR 6·1–9·3). The rate of breast cancer recurrence was lower for women allocated to an aromatase inhibitor than for women assigned to tamoxifen (RR 0·79, 95% CI 0·69–0·90, p=0·0005). The main benefit was seen in years 0–4 (RR 0·68, 99% CI 0·55–0·85; p<0·0001), the period when treatments differed, with a 3·2% (95% CI 1·8–4·5) absolute reduction in 5-year recurrence risk (6·9% vs 10·1%). There was no further benefit, or loss of benefit, in years 5–9 (RR 0·98, 99% CI 0·73–1·33, p=0·89) or beyond year 10. Distant recurrence was reduced with aromatase inhibitor (RR 0·83, 95% CI 0·71–0·97; p=0·018). No significant differences were observed between treatments for breast cancer mortality (RR 1·01, 95% CI 0·82–1·24; p=0·94), death without recurrence (1·30, 0·75–2·25; p=0·34), or all-cause mortality (1·04, 0·86–1·27; p=0·68). There were more bone fractures with aromatase inhibitor than with tamoxifen (227 [6·4%] of 3528 women allocated to an aromatase inhibitor vs 180 [5·1%] of 3502 women allocated to tamoxifen; RR 1·27 [95% CI 1·04–1·54]; p=0·017). Non-breast cancer deaths (30 [0·9%] vs 24 [0·7%]; 1·30 [0·75–2·25]; p=0·36) and endometrial cancer (seven [0·2%] vs 15 [0·3%]; 0·52 [0·22–1·23]; p=0·14) were rare. Using an aromatase inhibitor rather than tamoxifen in premenopausal women receiving ovarian suppression reduces the risk of breast cancer recurrence. Longer follow-up is needed to assess any impact on breast cancer mortality. Cancer Research UK, UK Medical Research Council.

AbstractObjectivesTo 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.DesignPopulation based observational cohort study.SettingRoutinely collected data from the National Cancer Registration and Analysis Service.ParticipantsAll 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 measuresAnnual breast cancer mortality rates and cumulative risks by time since diagnosis, calendar period of diagnosis, and nine characteristics of patients and tumours.ResultsFor 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.ConclusionsThese 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.

Anthracycline–taxane chemotherapy for early-stage breast cancer substantially improves survival compared with no chemotherapy. However, concerns about short-term and long-term side-effects of anthracyclines have led to increased use of taxane chemotherapy without anthracycline, which could compromise efficacy. We aimed to better characterise the benefits and risks of including anthracycline, and the comparative benefits of different anthracycline–taxane regimens. We did an individual patient-level meta-analysis of randomised trials comparing taxane regimens with versus without anthracycline, and updated our previous meta-analysis of anthracycline regimens with versus without taxane, as well as analysing 44 trials in six related comparisons. We searched databases, including MEDLINE, Embase, the Cochrane Library, and meeting abstracts to identify trials assessing anthracycline and taxane chemotherapy. Adjuvant or neoadjuvant trials were eligible if they began before Jan 1, 2012. Primary outcomes were breast cancer recurrence and cause-specific mortality. Log-rank analyses yielded first-event rate ratios (RRs) and CIs. 28 trials of taxane regimens with or without anthracycline were identified, of which 23 were deemed eligible, and 15 provided data on 18 103 women. Across all 15 trials that provided individual data, recurrence rates were 14% lower on average (RR 0·86, 95% CI 0·79–0·93; p=0·0004) with taxane regimens including anthracycline than those without. Non-breast cancer deaths were not increased but there was one additional acute myeloid leukaemia case per 700 women treated. The clearest reductions in recurrence were found when anthracycline was added concurrently to docetaxel plus cyclophosphamide versus the same dose of docetaxel plus cyclophosphamide (10-year recurrence risk 12·3% vs 21·0%; risk difference 8·7%, 95% CI 4·5–12·9; RR 0·58, 0·47–0·73; p<0·0001). 10-year breast cancer mortality in this group was reduced by 4·2% (0·4–8·1; p=0·0034). No significant reduction in recurrence risk was found for sequential schedules of taxane plus anthracycline when compared with docetaxel plus cyclophosphamide (RR 0·94, 0·83–1·06; p=0·30). For the analysis of anthracycline regimens with versus without taxane, 35 trials (n=52 976) provided individual patient data. Larger recurrence reductions were seen from adding taxane to anthracycline regimens when the cumulative dose of anthracycline was the same in each group (RR 0·87, 0·82–0·93; p<0·0001; n=11 167) than in trials with two-fold higher cumulative doses of non-taxane (mostly anthracycline) in the control group than in the taxane group (RR 0·96, 0·90–1·03; p=0·27; n=14 620). Direct comparisons between anthracycline and taxane regimens showed that a higher cumulative dose and more dose-intense schedules were more efficacious. The proportional reductions in recurrence for taxane plus anthracycline were similar in oestrogen receptor-positive and oestrogen receptor-negative disease, and did not differ by age, nodal status, or tumour size or grade. Anthracycline plus taxane regimens are most efficacious at reducing breast cancer recurrence and death. Regimens with higher cumulative doses of anthracycline plus taxane provide the greatest benefits, challenging the current trend in clinical practice and guidelines towards non-anthracycline chemotherapy, particularly shorter regimens, such as four cycles of docetaxel–cyclophosphamide. By bringing together data from almost all relevant trials, this meta-analysis provides a reliable evidence base to inform individual treatment decisions, clinical guidelines, and the design of future clinical trials. Cancer Research UK, UK Medical Research Council.

Trastuzumab targets the extracellular domain of the HER2 protein. Adding trastuzumab to chemotherapy for patients with early-stage, HER2-positive breast cancer reduces the risk of recurrence and death, but is associated with cardiac toxicity. We investigated the long-term benefits and risks of adjuvant trastuzumab on breast cancer recurrence and cause-specific mortality. We did a collaborative meta-analysis of individual patient data from randomised trials assessing chemotherapy plus trastuzumab versus the same chemotherapy alone. Randomised trials that enrolled women with node-negative or node-positive, operable breast cancer were included. We collected individual patient-level data on baseline characteristics, dates and sites of first distant breast cancer recurrence and any previous local recurrence or second primary cancer, and the date and underlying cause of death. Primary outcomes were breast cancer recurrence, breast cancer mortality, death without recurrence, and all-cause mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, oestrogen receptor (ER) status, and trial yielded first-event rate ratios (RRs). Seven randomised trials met the inclusion criteria, and included 13 864 patients enrolled between February, 2000, and December, 2005. Mean scheduled treatment duration was 14·4 months and median follow-up was 10·7 years (IQR 9·5 to 11·9). The risks of breast cancer recurrence (RR 0·66, 95% CI 0·62 to 0·71; p<0·0001) and death from breast cancer (0·67, 0·61 to 0·73; p<0·0001) were lower with trastuzumab plus chemotherapy than with chemotherapy alone. Absolute 10-year recurrence risk was reduced by 9·0% (95% CI 7·4 to 10·7; p<0·0001) and 10-year breast cancer mortality was reduced by 6·4% (4·9 to 7·8; p<0·0001), with a 6·5% reduction (5·0 to 8·0; p<0·0001) in all-cause mortality, and no increase in death without recurrence (0·4%, –0·3 to 1·1; p=0·35). The proportional reduction in recurrence was largest in years 0–1 after randomisation (0·53, 99% CI 0·46 to 0·61), with benefits persisting through years 2–4 (0·73, 0·62 to 0·85) and 5–9 (0·80, 0·64 to 1·01), and little follow-up beyond year 10. Proportional recurrence reductions were similar irrespective of recorded patient and tumour characteristics, including ER status. The more high risk the tumour, the larger the absolute reductions in 5-year recurrence (eg, 5·7% [95% CI 3·1 to 8·3], 6·8% [4·7 to 9·0], and 10·7% [7·7 to 13·6] in N0, N1–3, and N4+ disease). Adding trastuzumab to chemotherapy for early-stage, HER2-positive breast cancer reduces recurrence of, and mortality from, breast cancer by a third, with worthwhile proportional reductions irrespective of recorded patient and tumour characteristics. Cancer Research UK, UK Medical Research Council.