Purpose: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows noninvasive, in vivo measurements of tissue microvessel perfusion and permeability. We examined whether DCE-MRI done after two cycles of neoadjuvant chemotherapy could predict final clinical and pathologic response in primary breast cancers. Experimental Design: Thirty-seven patients with primary breast cancer, due to receive six cycles of neoadjuvant 5-fluorouracil, epirubicin and cyclophosphamide chemotherapy, were examined using DCE-MRI before neoadjuvant chemotherapy and after two cycles of treatment. Changes in DCE-MRI kinetic parameters (K trans , k ep , v e , MaxGd, rBV, rBF, MTT) were correlated with the final clinical and pathologic response to neoadjuvant chemotherapy.Test-retest variability was used to determine individual patient response. Results: Twenty-eight patients were evaluable for response (19 clinical responders and 9 nonresponders; 11 pathologic responders and 17 nonresponders). Changes in the DCE-MRI kinetic parameters K trans , k ep , MaxGd, rBV, and rBF were significantly correlated with both final clinical and pathologic response (P < 0.01). Change in K trans was the best predictor of pathologic nonresponse (area under the receiver operating characteristic curve, 0.93; sensitivity, 94%; specificity, 82%), correctly identifying 94% of nonresponders and 73% of responders. Change in MRIderived tumor size did not predict for pathologic response. Conclusion: Changes in breast tumor microvessel functionality as depicted by DCE-MRI early on after starting anthracycline-based neoadjuvant chemotherapy can predict final clinical and pathologic response. The ability to identify nonresponders early may allow the selection of patients who may benefit from a therapy change.

Primary systemic therapy (PST) for operable breast cancer enables the identification of in vivo biological markers that predict response to treatment. A total of 118 patients with T2 -4 N0 -1 M0 primary breast cancer received six cycles of anthracycline-based PST. Clinical and radiological response was assessed before and after treatment using UICC criteria. A grading system to score pathological response was devised. Diagnostic biopsies and postchemotherapy surgical specimens were stained for oestrogen (ER) and progesterone (PgR) receptor, HER-2 and cell proliferation (Ki-67). Clinical, radiological and pathological response rates were 78, 72 and 38%, respectively. There was a strong correlation between ER and PgR staining (Po0.0001). Higher Ki-67 proliferation indices were associated with PgRÀ tumours (median 28.3%, PgR þ 22.9%; P ¼ 0.042). There was no relationship between HER-2 and other biological markers. No single pretreatment or postchemotherapy biological parameter predicted response by any modality of assessment. In all, 10 tumours changed hormone receptor classification after chemotherapy (three ER, seven PgR); HER-2 staining changed in nine cases. Median Ki-67 index was 24.9% before and 18.1% after treatment (P ¼ 0.02); the median reduction in Ki-67 index after treatment was 21.2%. Tumours displaying 475% reduction in Ki-67 after chemotherapy were more likely to achieve a pathological response (77.8 vs 26.7%, P ¼ 0.004).

NCT01401166.

No abstract

Aim: Firstly, to quantify active healthcare professional (HCP) time and costs associated with subcutaneous (SC) administration of trastuzumab (Herceptin ® ) compared with the standard intravenous infusion (IV) in the treatment of patients with HER2-positive early breast cancer within the adjuvant PrefHer trial setting; secondly, to measure patient time in the care unit and patient infusion chair time for both routes of administration. Methods: A UK multi-centre prospective, observational Time and Motion study was conducted alongside the PrefHer trial (ClinicalTrials.gov id: NCT01401166). Trained observers measured the duration of each SC and IV related task that HCPs undertook and recorded patient time in the chemotherapy unit and infusion chair. The type and quantity of medical consumables used with each route of administration were also collected. Twenty-four patient episodes were recorded (12 SC, 12 IV). Mean total administration time was calculated as the mean sum of task times, both for IV and SC formulations. The mean cost of each route of administration was calculated as the mean cost of HCP time plus the mean cost of consumables used. HCP time was costed using Personal Social Services Research Unit. Consumables were costed using hospital pharmacy data and online sources. Results: Mean active HCP time for IV administration was 92.6 minutes compared with 24.6 minutes for SC administration. The mean cost for IV preparation and administration was £144.96 (£132.05 of HCP time and £12.92 of consumables) versus £33.15 (£31.99 of HCP time and £1.17 of consumables) for SC administration. Mean time spent in the care unit and in the infusion chair was 94.5 minutes and 75 minutes respectively for IV, and 30.3 minutes and 19.8 minutes for SC. SC administration of trastuzumab could translate to a time saving of 68 minutes (versus IV) with a total cost saving of £111.81 per patient episode. This equates to a potential saving of £2012.58 over a full course of adjuvant treatment (18 cycles). Conclusion: Substituting IV infusion with SC administration of trastuzumab may lead to a substantial reduction in active HCP time, patient chair and unit time, consumable use and overall costs. The reduced patient chair and unit time could provide increased capacity within existing resources.

Introduction Biological markers that reliably predict clinical or pathological response to primary systemic therapy early during a course of chemotherapy may have considerable clinical potential. This study evaluated changes in Ki-67 labeling index and apoptotic index (AI) before, during, and after neoadjuvant anthracycline chemotherapy.

Introduction: Adjuvant therapy in osteosarcoma (OS) and Ewing's sarcoma (ES) is primarily directed towards treatment of subclinical lung disease. Before the advent of modern intensive chemotherapy, lung irradiation was the only available adjuvant treatment. It has proven biological activity and low morbidity. There is, however, a wide variation in its application between centres. This systematic review aims to define the evidence to support the use of lung irradiation in these diseases.Design: A review of trials published between 1966 and 2000 was undertaken to determine the evidence for the use of pulmonary irradiation in OS and ES.Results: Several small series of prophylactic lung irradiation (PLI) have been reported, most from over 20 years ago. These studies support the theoretical basis for the use of PLI in both OS and ES. Few randomised studies have been performed which include PLI. In OS, studies demonstrated a trend in favour of PLI compared with no adjuvant treatment and, subsequently, a level of benefit similar to that achieved with chemotherapy, but no additive effect. No studies have used PLI in addition to current standard chemotherapy regimens, or evaluated its use after successful metastatectomy. In ES, only one randomised study has addressed the role of PLI, in a comparison with vincristine, actinomycin D and cyclophosphamide combination chemotherapy with or without doxorubicin. Prolonged follow-up favoured four-drug chemotherapy. Retrospective reports from large cooperative groups suggest that the addition of whole-lung radiotherapy (WLRT) improves outcome in ES patients presenting with pulmonary metastases. However, there are no randomised study data to support this. Conclusions:Further randomised studies are necessary to clarify the role of PLI in addition to current standard chemotherapy regimens, or its use after successful metastasectomy in patients with OS. In patients with localised ES adjuvant chemotherapy appears to be superior to PLI alone, while there is little evidence to support treatment with WLRT in patients who present with pulmonary metastases.

Pre-surgical studies allow study of the relationship between mutations and response of oestrogen receptor-positive (ER+) breast cancer to aromatase inhibitors (AIs) but have been limited to small biopsies. Here in phase I of this study, we perform exome sequencing on baseline, surgical core-cuts and blood from 60 patients (40 AI treated, 20 controls). In poor responders (based on Ki67 change), we find significantly more somatic mutations than good responders. Subclones exclusive to baseline or surgical cores occur in ∼30% of tumours. In phase II, we combine targeted sequencing on another 28 treated patients with phase I. We find six genes frequently mutated: PIK3CA, TP53, CDH1, MLL3, ABCA13 and FLG with 71% concordance between paired cores. TP53 mutations are associated with poor response. We conclude that multiple biopsies are essential for confident mutational profiling of ER+ breast cancer and TP53 mutations are associated with resistance to oestrogen deprivation therapy.