Identification and Validation of an Anthracycline/Cyclophosphamide–Based Chemotherapy Response Assay in Breast Cancer

Background: There is no method routinely used to predict response to anthracycline and cyclophosphamide–based chemotherapy in the clinic; therefore patients often receive treatment for breast cancer with no benefit. Loss of the Fanconi anemia/BRCA (FA/BRCA) DNA damage response (DDR) pathway occurs in approximately 25% of breast cancer patients through several mechanisms and results in sensitization to DNA-damaging agents. The aim of this study was to develop an assay to detect DDR-deficient tumors associated with loss of the FA/BRCA pathway, for the purpose of treatment selection.

Methods: DNA microarray data from 21 FA patients and 11 control subjects were analyzed to identify genetic processes associated with a deficiency in DDR. Unsupervised hierarchical clustering was then performed using 60 BRCA1/2 mutant and 47 sporadic tumor samples, and a molecular subgroup was identified that was defined by the molecular processes represented within FA patients. A 44-gene microarray-based assay (the DDR deficiency assay) was developed to prospectively identify this subgroup from formalin-fixed, paraffin-embedded samples. All statistical tests were two-sided.

Results: In a publicly available independent cohort of 203 patients, the assay predicted complete pathologic response vs residual disease after neoadjuvant DNA-damaging chemotherapy (5-fluorouracil, anthracycline, and cyclophosphamide) with an odds ratio of 3.96 (95% confidence interval [Cl] =1.67 to 9.41; P = .002). In a new independent cohort of 191 breast cancer patients treated with adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, a positive assay result predicted 5-year relapse-free survival with a hazard ratio of 0.37 (95% Cl = 0.15 to 0.88; P = .03) compared with the assay negative population.

Conclusions: A formalin-fixed, paraffin-embedded tissue-based assay has been developed and independently validated as a predictor of response and prognosis after anthracycline/cyclophosphamide–based chemotherapy in the neoadjuvant and adjuvant settings. These findings warrant further validation in a prospective clinical study.

Career choices on graduation--a study of recent graduates from University College Cork

INTRODUCTION: Irish dental graduates are eligible to enter general dental practice immediately after qualification. Unlike their United Kingdom counterparts, there is no requirement to undertake vocational training (VT) or any pre-registration training. VT is a mandatory 12-month period for all UK dental graduates who wish to work within the National Health Service. It provides structured, supervised experience in training practices and through organised study days.

AIMS: This study aimed to profile the career choices made by recent dental graduates from UCC. It aimed to record the uptake of VT and associate posts, and where the graduates gained employment.

METHODOLOGY: A self-completion questionnaire was developed and circulated electronically to recent graduates from UCC. An existing database of email addresses was used and responses were returned by post or by email. A copy of the questionnaire used is included as Appendix 1.

RESULTS: Questionnaires were distributed over an eight-week period and 142 were returned, giving a response rate of 68.90%. Responses were gathered from those who graduated between 2001 and 2007; however, the majority came from more recent classes. Overall, the majority of graduates took up associate positions after qualification (71.8%) with smaller numbers undertaking VT (28.2%). Increasing numbers have entered VT in recent years, including 54.3% from the class of 2007. Overall, the majority of graduates initially took up positions in England (43%); however, in recent times more have been employed in Scotland. Subsequent work profiles of the graduates illustrate that the majority are now working as associates in general practice (51.4%) and in Ireland (54.2%).

CONCLUSIONS: There has been an increase in the proportion of UCC graduates undertaking VT. Graduates tended to move away from Ireland initially to gain employment. There has been a shift away from employment in England towards Scotland where the majority of new UCC graduates are now initially employed. The majority of graduates returned to Ireland for employment after the initial move away.