Postoperative radiotherapy in women with early operable breast cancer (Scottish Breast Conservation Trial): 30-year update of a randomised, controlled, phase 3 trial.

BACKGROUND: Breast-conserving surgery, adjuvant systemic therapy, and radiotherapy are the standard of care for most women with early breast cancer. There are few reports of clinical outcomes beyond the first decade of follow-up of randomised trials comparing breast-conserving surgery with or without radiotherapy. We present a 30-year update of the Scottish Breast Conservation Trial. METHODS: In this randomised, controlled, phase 3 trial across 14 hospitals in Scotland, women aged younger than 70 years with early breast cancer (tumours ≤4 cm [T1 or T2 and N0 or N1]) were included. They underwent breast-conserving surgery (1 cm margin) with axillary node sampling or clearance. Oestrogen receptor (ER)-rich patients (≥20 fmol/mg protein) received 20 mg oral tamoxifen daily for 5 years. ER-poor patients (<20 fmol/mg protein) received chemotherapy (cyclophosphamide 600 mg/m2, methotrexate 50 mg/m2, and fluorouracil 600 mg/m2 every 21 days intravenously in eight courses). Stratification was by menstrual status (within or more than 12 months from last menstrual period) and ER status (oestrogen concentration ≥20 fmol/mg protein, <20 fmol/mg protein, or unknown) and patients were randomly assigned (1:1) to high-dose (50 Gy in 20-25 fractions) local or locoregional radiotherapy versus no radiotherapy. No blinding was possible due to the nature of the treatment. We report the primary endpoint of the original trial, ipsilateral breast tumour recurrence, and the co-primary endpoint, overall survival. Clinical outcomes were compared by the log-rank test. Hazard ratios (HRs) are reported, with no radiotherapy as the reference group. Failures of the proportional hazards assumption are reported if significant. All analyses are by intention to treat. FINDINGS: Between April 1, 1985, and Oct 2, 1991, 589 patients were enrolled and randomly assigned to the two treatment groups (293 to radiotherapy and 296 to no radiotherapy). After exclusion of four ineligible patients (two in each group), there were 291 patients in the radiotherapy group and 294 patients in the no radiotherapy group. Median follow-up was 17·5 years (IQR 8·4-27·9). Ipsilateral breast tumour recurrence was significantly lower in the radiotherapy group than in the no radiotherapy group (46 [16%] of 291 vs 107 [36%] of 294; HR 0·39 [95% CI 0·28-0·55], p<0·0001). Although there were differences in the hazard rate for ipsilateral breast tumour recurrence in the first decade after treatment (HR 0·24 [95% CI 0·15-0·38], p<0·0001), subsequent risks of ipsilateral breast tumour recurrence were similar in both groups (0·98 [0·54-1·79], p=0·95). There was no difference in overall survival between the two groups (median 18·7 years [95% CI 16·5-21·5] in the no radiotherapy group vs 19·2 years [16·9-21·3] in the radiotherapy group; HR 1·08 [95% CI 0·89-1 ·30], log-rank p=0·43). INTERPRETATION: Our findings suggest that patients whose biology predicts a late relapse a decade or more after breast-conserving surgery for early breast cancer might gain little from adjuvant radiotherapy. FUNDING: Breast Cancer Institute (part of Edinburgh and Lothian Health Foundation) and PFS Genomics (now part of Exact Sciences).

Adjunctive Statistical Standardization of Adjuvant Estrogen Receptor and Progesterone Receptor in Canadian Cancer Trials Group MA.27 Postmenopausal Breast Cancer Trial of Exemestane Versus Anastrozole.

PURPOSE: ASCO/College of American Pathologists guidelines recommend reporting estrogen receptor (ER) and progesterone receptor (PgR) as positive with (1%-100%) staining. Statistically standardized quantitated positivity could indicate differential associations of positivity with breast cancer outcomes. METHODS: MA.27 (ClinicalTrials.gov identifier: NCT00066573) was a phase III adjuvant trial of exemestane versus anastrozole in postmenopausal women with early-stage breast cancer. Immunochemistry ER and PgR HSCORE and % positivity (%+) were centrally assessed by machine image quantitation and statistically standardized to mean 0 and standard deviation (SD) 1 after Box-Cox variance stabilization transformations of square for ER; for PgR, (1) natural logarithm (0.1 added to 0 HSCOREs and 0%+) and (2) square root. Our primary end point was MA.27 distant disease-free survival (DDFS) at a median 4.1-year follow-up, and secondary end point was event-free survival (EFS). Univariate survival with cut points at SDs about a mean of 0 (≤-1; (-1, 0]; (0, 1]; >1) was described with Kaplan-Meier plots and examined with Wilcoxon (Peto-Prentice) test statistic. Adjusted Cox multivariable regressions had two-sided Wald tests and nominal significance P < .05. RESULTS: Of 7,576 women accrued, 3,048 women's tumors had machine-quantitated image analysis results: 2,900 (95%) for ER, 2,726 (89%) for PgR, and 2,582 (85% of 3,048) with both ER and PgR. Higher statistically standardized ER and PgR HSCORE and %+ were associated with better univariate DDFS and EFS (P < .001). In multivariable assessments, ER HSCORE and %+ were not significantly associated (P = .52-.88) with DDFS in models with PgR, whereas higher PgR HSCORE and %+ were significantly associated with better DDFS (P = .001) in models with ER. CONCLUSION: Adjunctive statistical standardization differentiated quantitated levels of ER and PgR. Patients with higher ER- and PgR-standardized units had superior DDFS compared with those with HSCOREs and %+ ≤-1.

Preparing Institutions to Implement Harmonized Medicine and Nursing Curricula Through the Use of Cross-Institutional Faculty Developers.

Background: Effective implementation of new curricula requires faculty to be knowledgeable about curriculum goals and have the appropriate pedagogical skills to implement the curriculum, even more so if the new curriculum is being deployed at multiple institutions. In this paper, we describe the process of creating a common faculty development program to train cross-institutional faculty developers to support the implementation of national harmonized medicine and nursing curricula. Methods: A five-step approach was used, including a cross-institutional needs assessment survey for faculty development needs, the development of a generic faculty development program, the identification and training of cross-institutional faculty educators, and the implementation of cross-institutional faculty capacity-building workshops. Results: A list of common cross-cutting faculty development needs for teaching and learning was identified from the needs assessment survey and used to develop an accredited, cross-institutional faculty development program for competency-based learning and assessment. A total of 24 cross-institutional faculty developers were identified and trained in 8 core learning and assessment workshops. A total of 18 cross-institutional and 71 institutional workshops were conducted, of which 1292 faculty members and 412 residents were trained, and three cross-institutional educational research projects were implemented. Conclusion: The success attained in this study shows that the use of cross-institutional faculty developers is a viable model and sustainable resource that can be used to support the implementation of harmonized national curricula.

Geographic variation of mutagenic exposures in kidney cancer genomes.

International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden1. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence2. Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.

Efficacy of mobile phone intervention to increase male partner antenatal care attendance for HIV testing in Moshi municipal, Tanzania: a randomized controlled trial.

BACKGROUND: HIV partner counselling and testing in antenatal care (ANC) is a crucial strategy to raise the number of males who know their HIV status. However, in many settings like Tanzania, male involvement in antenatal care remains low, and there is a definite need for innovative strategies to increase male partner involvement. This study was designed to evaluate the efficacy of mobile phone intervention increase male partner ANC attendance for HIV testing in Moshi municipal, Tanzania. METHODS: Between April and July 2022, we enrolled pregnant women presenting to a first ANC visit at Majengo and St. Joseph reproductive health facilities without their male partners. Eligible pregnant women were randomly assigned to invitation of their male partners either via phone calls, text messages from clinic staff and verbal invites from pregnant partners (intervention arm) or verbal invites only from the pregnant partners (control arm). Neither healthcare provider nor participant were blinded. The primary outcome was the proportion of male partners who attended ANC with their pregnant partners during a follow-up period of two consecutive visits. The secondary outcome measure was HIV testing among male partners following the invitation. Participants were analyzed as originally assigned (intention to treat). RESULTS: A total of 350 pregnant women presenting to ANC for the first time were enrolled, with 175 women enrolled in each arm. The efficacy of male attendance with their pregnant women following the invitations was 83.4% (147/175) in the intervention arm and 46.3% (81/175) in the control arm. Overall, the results suggest a positive and statistically significant average treatment effect among men who received mobile phone intervention on ANC attendance. For the secondary outcome, the percent of male partners who accepted HIV counselling and testing was 99.3% (146/147) in the intervention arm and 93.8% (76/81) in the control arm. Married men were having higher odds of ANC attendance compared with single men (aOR:6.40(3.26-12.56), Males with multigravida women were having lower odds of ANC attendance compared with primigravida women (aOR:0.17(0.09-0.33). CONCLUSION: The study demonstrates that supplementing verbal invitations with mobile phone calls and text messages from clinic staff can significantly increase male partner ANC attendance and HIV testing. This combined approach is recommended in improving ANC attendance and HIV testing of male partners who do not accompany their pregnant partners to antenatal clinics in the first visits. TRIAL REGISTRATION: PACTR202209769991162.

Validation of the Prognostic Performance of Breast Cancer Index in Hormone Receptor-Positive Postmenopausal Breast Cancer Patients in the TEAM Trial.

PURPOSE: Patients with early-stage hormone receptor-positive (HR+) breast cancer face a prolonged risk of recurrence even after adjuvant endocrine therapy. The Breast Cancer Index (BCI) is significantly prognostic for overall (0-10 years) and late (5-10 years) distant recurrence (DR) risk in N0 and N1 patients. Here, BCI prognostic performance was evaluated in HR+ postmenopausal women from the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial. EXPERIMENTAL DESIGN: 3,544 patients were included in the analysis (N = 1,519 N0, N = 2,025 N+). BCI risk groups were calculated using pre-specified cutoff points. Kaplan-Meier analyses and log-rank tests were used to assess the prognostic significance of BCI risk groups based on DR. Hazard ratios (HR) and confidence intervals (CI) were calculated using Cox models with and without clinical covariates. RESULTS: For overall 10-year DR, BCI was significantly prognostic in Ni0 (N = 1,196) and N1 (N = 1,234) patients who did not receive prior chemotherapy (P < 0.001). In patients who were DR-free for 5 years, 10-year late DR rates for low- and high-risk groups were 5.4% and 9.3% (N0 cohort, N = 1,285) and 4.8% and 12.2% (N1 cohort, N = 1,625) with multivariate HRs of 2.25 (95% CI, 1.30-3.88; P = 0.004) and 2.67 (95% CI, 1.53-4.63; P < 0.001), respectively. Late DR performance was substantially improved using previously optimized cutoff points, identifying BCI low-risk groups with even lower 10-year late DR rates of 3.8% and 2.7% in N0 and N1 patients, respectively. CONCLUSIONS: The TEAM trial represents the largest prognostic validation study for BCI to date and provides a more representative assessment of late DR risk to guide individualized treatment decision-making for HR+ patients with early-stage breast cancer.

Implementation of a Learning Management System for Medical Students: A Case Study of Kilimanjaro Christian Medical University College.

This article was migrated. The article was marked as recommended. Learning Management Systems (LMS) are powerful tools for the organization and presentation of curricular learning materials, for monitoring of student and faculty members performance, and for overall quality control. However, there is limited evidence regarding the acceptance and performance of LMS in Africa. This manuscript describes the implementation, the outcomes, and the challenges of the first five years of a LMS at the Kilimanjaro Christian Medical University College (KCMUCo). The LMS has been fully adopted into KCMUCo curriculum and deployed to 1356 students. It has been demonstrated to enhance learning with strength of consensus measure of 84% for basic sciences and 78% for clinical classes. 80% of faculty members have been satisfied with the use of LMS. Electronic assessment has become an obligatory platform for theory examinations. LMS adoption may improve education outcomes at other medical schools in Tanzania and sub-Saharan Africa.