Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer : meta-analysis of individual patient data from ten randomised trials

Background Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials. Methods We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality). Findings Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5-14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21.4% for NACT versus 15.9% for adjuvant chemotherapy (5.5% increase [95% CI 2.4-8.6]; rate ratio 1.37 [95% CI 1.17-1.61]; p = 0.0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38.2% for NACT vs 38.0% for adjuvant chemotherapy; rate ratio 1.02 [95% CI 0.92-1.14]; p = 0.66), breast cancer mortality (34.4% vs 33.7%; 1.06 [0.95-1.18]; p = 0.31), or death from any cause (40.9% vs 41.2%; 1.04 [0.94-1.15]; p = 0.45). Interpretation Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered-eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy. Copyright (c) The Author(s). Published by Elsevier Ltd.Peer reviewe

The Barker hypothesis

The Barker hypothesis proposed that adverse nutrition in early life, including prenatally as measured by birth weight, increased susceptibility to the metabolic syndrome which includes obesity, diabetes, insulin insensitivity, hypertension, and hyperlipidemia and complications that include coronary heart disease and stroke. Periods of rapid postnatal growth associated with high-energy intake seem to be risk factors, along with a high-energy western diet. Theories proposing the mechanism of this association include the thrifty gene, bet-hedging, fetal predictive adaptive response, and drifty phenotype hypotheses. The cause of metabolic syndrome is likely to be multifactorial, with many nuclear DNA and cellular RNA sequences acting in concert with environmental influences. Epidemiological data in humans and experimental data indicate that transgenerational epigenetic inheritance is a possible mechanism where a history of starvation or deprivation during early life is seen in a grandparent and transgenerational effects are seen in their grandchildren. It remains to be seen whether this is mediated by heritable RNA sequences, or by acquired, possibly mosaic mutations in DNA coding for example for regulatory RNAs. Recent research has raised the possibility that the nature and quantity of gastrointestinal microorganisms (microbiota) can be modified by diet and conversely can modify an animal's metabolic program. As the microbiota is inherited largely from the mother, modification of her nutrition, health before and during pregnancy, and mode of delivery could influence the child's microbiota, introducing further potential avenues to improve the prevention, reduction of complications, and treatment of malnutrition and metabolic syndrome