BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population.

BACKGROUND: BEECH investigated the efficacy of capivasertib (AZD5363), an oral inhibitor of AKT isoforms 1-3, in combination with the first-line weekly paclitaxel for advanced or metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, and in a phosphoinositide 3-kinase, catalytic, alpha polypeptide mutation sub-population (PIK3CA+). PATIENTS AND METHODS: BEECH consisted of an open-label, phase Ib safety run-in (part A) in 38 patients with advanced breast cancer, and a randomised, placebo-controlled, double-blind, phase II expansion (part B) in 110 women with ER+/HER2- metastatic breast cancer. In part A, patients received paclitaxel 90 mg/m2 (days 1, 8 and 15 of a 28-day cycle) with capivasertib taken twice daily (b.i.d.) at two intermittent ascending dosing schedules. In part B, patients were randomly assigned, stratified by PIK3CA mutation status, to receive paclitaxel with either capivasertib or placebo. The primary end point for part A was safety to recommend a dose and schedule for part B; primary end points for part B were progression-free survival (PFS) in the overall and PIK3CA+ sub-population. RESULTS: Capivasertib was well tolerated, with a 400 mg b.i.d. 4 days on/3 days off treatment schedule selected in part A. In part B, median PFS in the overall population was 10.9 months with capivasertib versus 8.4 months with placebo [hazard ratio (HR) 0.80; P = 0.308]. In the PIK3CA+ sub-population, median PFS was 10.9 months with capivasertib versus 10.8 months with placebo (HR 1.11; P = 0.760). Based on the Common Terminology Criteria for Adverse Event v4.0, the most common grade ≥3 adverse events in the capivasertib group were diarrhoea, hyperglycaemia, neutropoenia and maculopapular rash. Dose intensity of paclitaxel was similar in both groups. CONCLUSIONS: Capivasertib had no apparent impact on the tolerability and dose intensity of paclitaxel. Adding capivasertib to weekly paclitaxel did not prolong PFS in the overall population or PIK3CA+ sub-population of ER+/HER2- advanced/metastatic breast cancer patients.ClinicalTrials.gov: NCT01625286.

Early ctDNA dynamics as a surrogate for progression-free survival in advanced breast cancer in the BEECH trial.

BACKGROUND: Dynamic changes in circulating tumour DNA (ctDNA) levels may predict long-term outcome. We utilised samples from a phase I/II randomised trial (BEECH) to assess ctDNA dynamics as a surrogate for progression-free survival (PFS) and early predictor of drug efficacy. PATIENTS AND METHODS: Patients with estrogen receptor-positive advanced metastatic breast cancer (ER+ mBC) in the BEECH study, paclitaxel plus placebo versus paclitaxel plus AKT inhibitor capivasertib, had plasma samples collected for ctDNA analysis at baseline and at multiple time points in the development cohort (safety run-in, part A) and validation cohort (randomised, part B). Baseline sample ctDNA sequencing identified mutations for longitudinal analysis and mutation-specific digital droplet PCR (ddPCR) assays were utilised to assess change in ctDNA abundance (allele fraction) between baseline and 872 on-treatment samples. Primary objective was to assess whether early suppression of ctDNA, based on pre-defined criteria from the development cohort, independently predicted outcome in the validation cohort. RESULTS: In the development cohort, suppression of ctDNA was apparent after 8 days of treatment (P = 0.014), with cycle 2 day 1 (4 weeks) identified as the optimal time point to predict PFS from early ctDNA dynamics. In the validation cohort, median PFS was 11.1 months in patients with suppressed ctDNA at 4 weeks and 6.4 months in patients with high ctDNA (hazard ratio = 0.20, 95% confidence interval 0.083-0.50, P < 0.0001). There was no difference in the level of ctDNA suppression between patients randomised to capivasertib or placebo overall (P = 0.904) nor in the PIK3CA mutant subpopulation (P = 0.071). Clonal haematopoiesis of indeterminate potential (CHIP) was evident in 30% (18/59) baseline samples, although CHIP had no effect on tolerance of chemotherapy nor on PFS. CONCLUSION: Early on-treatment ctDNA dynamics are a surrogate for PFS. Dynamic ctDNA assessment has the potential to substantially enhance early drug development. CLINICAL REGISTRATION NUMBER: NCT01625286.

Educating future physicians for Ontario: phase II.

In 1990, a collaborative project was launched to determine what the people of Ontario expect of their physicians and how the programs that prepare future physicians should be changed in response. The project, called Educating Future Physicians for Ontario (EFPO), brought together the five Ontario medical schools, the Council of Ontario Faculties of Medicine (COFM); a nonprofit, charitable organization, Associated Medical Services (AMS); and the Ontario Ministry of Health. The first phase ran for five years and was described in the November 1998 issue of Academic Medicine. After an external review, the project was continued for a second phase (EFPO II) for four more years until December 1998; that second phase is the topic of this article. EFPO II (1) focused more on residents' education; (2) emphasized four of the EFPO I-created physician roles in project activities; (3) maintained the province-wide, inter-institutional medical education framework of phase I, but fostered greater involvement of the seven sites (five medical schools and two regional health centers) in project activities; (4) stressed five project components (e.g., needs assessment and community partnerships) and worked for collaboration among components at all sites; (5) enhanced the original EFPO I Fellowship Program by adding residents and community fellows to the existing fellowships and by initiating leadership development activities, all of which bode well for the future leadership of medical education in Ontario. Students and residents played a vital role in EPFO II. Most of EFPO II's objectives were met, but the overall view of external reviewers was that the project was less successful than EFPO I. For example, the impact on clinical education, especially residency education, was less than anticipated. On the other hand, the project helped encourage the wide adoption of the eight physician roles that originated in EFPO I and advanced faculty development and assessment activities based on these roles. A third phase of EFPO concerning continuing medical education was planned, but support was not available. However, one of the funders will continue to support the successful fellowship and leadership program and the provincial education network for the next three years. Overall, the two phases of EFPO substantially modified medical education in Ontario to make it more responsive to evolving social needs.

Content in context: medical education and society's needs.

Many reports have emphasized the need to reform medical education to bring it into harmony with society's needs and expectations. Although much effort has been expended over several decades, many believe that reform initiatives have not successfully modified physicians' behaviors and attitudes. More recently, two major projects--Educating Future Physicians for Ontario and the Medical School Objectives Project--have identified physician roles and attributes necessary to meet societal needs. These efforts have provided a substantial framework upon which the content and conduct of a more relevant kind of medical education can be built. In order to implement real change, however, medical schools must (1) take the long view, making reform part of the entire continuum of medical education; (2) ensure that faculty physicians teach by example; (3) change student assessments to reflect new educational objectives; and (4) reallocate resources to support a changed curriculum.

Educating future physicians for Ontario.

In 1987, Ontario's physicians conducted a strike, ultimately not successful, over the issue of "extra billing." The fact that the Ontario public did not support this action reflected a major gap between the profession's view of itself and the public's view of the profession. In 1990, the province's five medical schools launched a collaborative project to determine more specifically what the people of Ontario expect of their physicians, and how the programs that prepare future physicians should be changed in response. The authors report on the first five years of that ongoing project. Consumer groups were asked to state their views concerning the current roles of physicians, future trends that would affect these roles, changes in roles they wished to see, and suggestions for changes in medical education. Methods used included focus groups, key informant interviews, an extensive literature review, and surveys, including a survey of health professionals. Concurrently, inter-university working groups prepared tools and strategies for strengthening faculty development, assessing student performance, and preparing future leadership for Ontario's medical education system. Eight specific physician roles were identified: medical expert, communicator, collaborator, health advocate, learner, manager ("gatekeeper"), scholar, and "physician as person." Educational strategies to help medical students learn to assume these eight roles were then incorporated into the curricula of the five participating medical schools. The authors conclude that the project shows that it is feasible to learn specifically what society expects of its physicians, to integrate this knowledge into the process of medical education reform, and to implement major curriculum changes through a collaborative, multi-institutional consortium within a single geopolitical jurisdiction.

Demand-side medical education: educating future physicians for Ontario.

Initiated by Associated Medical Services (AMS), Educating Future Physicians for Ontario is a 5-year collaborative project whose overall goal is to make medical education in Ontario more responsive to that province's evolving health needs. It is supported by AMS, the five universities with medical schools or academic health sciences centres and the Ontario Ministry of Health. The project's five objectives are to (a) define the health needs and expectations of the public as they relate to the training of physicians, (b) prepare the educators of future physicians, (c) assess medical students' competencies, (d) support related curricular innovations and (e) develop ongoing leadership in medical education. There are several distinctive features: a focus on "demand-side" considerations in the design of curricula, collaboration within a geopolitical jurisdiction (Ontario), implementation rather than recommendation, a systematic project-evaluation plan and agreement as to defined project outcomes, in particular the development of institutional mechanisms of curriculum renewal as health needs and expectations evolve.

The clinical teaching unit in transition.

The clinical teaching unit (CTU), a distinctively Canadian concept, has served Canadian academic medicine well over the past 30 years. Times have changed considerably since the concept was first defined by the Association of Canadian Medical Colleges in 1962. Many proposals and ideas of Evans, Chute and Morley in their description of the CTU, clinical education and the practice of medicine remain relevant today. The concept of learning by doing, under supervision, in a relatively controlled academic environment is still valid. However, we must either expand our concept of the traditional CTU to make it consistent with the contemporary broad practice of medicine or maintain the current model as complementary, but not necessarily central, to an expanded paradigm of clinical education.

Effective in-training evaluation.

Effective in-training evaluation can significantly enhance learning for both undergraduate and postgraduate medical students. The importance of ongoing assessment must be understood and supported by clinical teachers, and their involvement in effective evaluation requires time and effort. In-training evaluation can be both informal and formal and embrace a wide variety of methods. Self-evaluation by students should be emphasized as an important part of the in-training evaluation process. Clearly stated educational objectives, understood by both teachers and students, are essential. The use of constructive and supportive feedback adds considerably to clinical learning. Fair and forthright evaluation is of special importance when dealing with poor student performance.

Accreditation of specialty residency programmes in Canada.

The accreditation process gives assurance to a number of individuals and groups about the quality of approved programmes. It is based on principles that have evolved over time. The process of the Royal College of Physicians and Surgeons of Canada is based upon a set of nine explicitly stated standards, each amplified by a detailed interpretation. On-site surveys conducted at regular intervals by peers, with active involvement of the teachers and students being surveyed and using checks and balances with respect to information obtained and decisions made are major characteristics of the Canadian accreditation process.