Adele Francis

Comparing Breast Cancer Multiparameter Tests in the OPTIMA Prelim Trial: No Test Is More Equal Than the Others

BACKGROUND Previous reports identifying discordance between multiparameter tests at the individual patient level have been largely attributed to methodological shortcomings of multiple in silico studies. Comparisons between tests, when performed using actual diagnostic assays, have been predicted to demonstrate high degrees of concordance. OPTIMA prelim compared predicted risk stratification and subtype classification of different multiparameter tests performed directly on the same population. METHODS Three hundred thirteen women with early breast cancer were randomized to standard (chemotherapy and endocrine therapy) or test-directed (chemotherapy if Oncotype DX recurrence score >25) treatment. Risk stratification was also determined with Prosigna (PAM50), MammaPrint, MammaTyper, NexCourse Breast (IHC4-AQUA), and conventional IHC4 (IHC4). Subtype classification was provided by Blueprint, MammaTyper, and Prosigna. RESULTS Oncotype DX predicted a higher proportion of tumors as low risk (82.1%, 95% confidence interval [CI] = 77.8% to 86.4%) than were predicted low/intermediate risk using Prosigna (65.5%, 95% CI = 60.1% to 70.9%), IHC4 (72.0%, 95% CI = 66.5% to 77.5%), MammaPrint (61.4%, 95% CI = 55.9% to 66.9%), or NexCourse Breast (61.6%, 95% CI = 55.8% to 67.4%). Strikingly, the five tests showed only modest agreement when dichotomizing results between high vs low/intermediate risk. Only 119 (39.4%) tumors were classified uniformly as either low/intermediate risk or high risk, and 183 (60.6%) were assigned to different risk categories by different tests, although 94 (31.1%) showed agreement between four of five tests. All three subtype tests assigned 59.5% to 62.4% of tumors to luminal A subtype, but only 121 (40.1%) were classified as luminal A by all three tests and only 58 (19.2%) were uniformly assigned as nonluminal A. Discordant subtyping was observed in 123 (40.7%) tumors. CONCLUSIONS Existing evidence on the comparative prognostic information provided by different tests suggests that current multiparameter tests provide broadly equivalent risk information for the population of women with estrogen receptor (ER)-positive breast cancers. However, for the individual patient, tests may provide differing risk categorization and subtype information.

The LORIS Trial: Addressing Overtreatment of Ductal Carcinoma In Situ

An unforeseen consequence of the introduction of mammographic breast screening has been the marked increase in the number of women diagnosed with ductal carcinoma in situ (DCIS) [1,2]. In 2009–2010, 2830 women were diagnosed with in situ carcinoma through the National Health Service Breast Screening Programme (NHSBSP) [3]. Screen-detected DCIS now accounts for 20% of ‘cancers’ identified through breast screening. However, the intent of breast screening programmes was to detect early invasive cancer, not to identify DCIS.

Selecting breast cancer patients for chemotherapy: the opening of the UK OPTIMA trial.

The mortality from breast cancer has improved steadily over the past two decades, in part because of the increased use of more effective adjuvant therapies. Thousands of women are routinely treated with intensive chemotherapy, which can be unpleasant, is expensive and is occasionally hazardous. Oncologists have long known that some of these women may not need treatment, either because they have a low risk of relapse or because they have tumour biology that makes them less sensitive to chemotherapy and more suitable for early adjuvant endocrine therapy. There is an urgent need to improve patient selection so that chemotherapy is restricted to those patients who will benefit from it. Here we review the emerging technologies that are available for improving patient selection for chemotherapy. We describe the OPTIMA trial, which has just opened to recruitment in the UK, is the latest addition to trials in this area, and is the first to focus on the relative cost-effectiveness of alternate predictive assays.

Low grade Ductal Carcinoma in situ (DCIS): How best to describe it?

BACKGROUND In the absence of definitive data about the natural history of DCIS the appropriateness of describing DCIS as cancer is controversial. METHODS We conducted a survey amongst British Breast Group (BBG) members, to determine which descriptions of DCIS were deemed most accurate and appropriate. RESULTS 54/73 (74%) attendees completed the survey: A majority (34/54; 63%) said they would be comfortable using the description that explained DCIS as abnormal cells in the milk ducts that had not spread into other breast tissue and which did not need urgent treatment as if it was breast cancer and this description was overall the most preferred (24/54; 44%). CONCLUSIONS Little consensus exists regarding how best to explain low grade DCIS to patients.

HER2 testing for breast carcinoma: recommendations for rapid diagnostic pathways in clinical practice

Human epidermal growth factor receptor 2 (HER2) testing is required for newly diagnosed breast cancer and advised for recurrent and metastatic breast cancer, to determine treatment planning using HER2-directed therapy in the neoadjuvant, adjuvant and advanced disease settings. Wide variation, nationally, in the turnaround time for HER2 testing may hinder equity of access for patients to both clinical trials and the timely implementation of HER2-directed therapy particularly in the neo-adjuvant setting. Process mapping from three recognised laboratories in the UK was applied to the logistics of HER2 testing in different geographic hub and spoke models. Consequently, recommendations for HER2 testing likely to facilitate access to clinical trials and timely patient care are presented.

Macroscopic handling and reporting of breast cancer specimens pre- and post-neoadjuvant chemotherapy treatment: review of pathological issues and suggested approaches.

Neoadjuvant chemotherapy (NACT) is used increasingly in the treatment of invasive breast cancer and presents challenges for the pathologist in the handling and interpretation of tissues. Potential issues include pathological identification and localization of the residual tumour site; how best to assess pathological response (given the diversity of scoring systems described); the timing and assessment of axillary node biopsy; and the value of retesting any residual tumour for dissonance between core biopsy and post‐treatment residual cancer cells for biomarker expression such as oestrogen and progesterone receptors and human epidermal growth factor receptor 2 (HER2). The role of the pathologist is critical in modern NACT approaches to breast cancer and is likely to remain challenging as novel agents and newer biomarkers become available. In this manuscript we review these issues and describe some practical approaches to handling and reporting these samples in the routine histopathology laboratory.

Abstract OT2-3-01: The LORIS trial: A multicentre, randomized phase III trial of standard surgery versus active monitoring in women with newly diagnosed low risk ductal carcinoma in situ

Background: The independent review of the UK National Health Service Breast Screening Programme reported recently on the benefits and harms of breast screening (The Lancet, Volume 380, Issue 9855, Pages 1778 - 1786, 17 November 2012). This concluded that breast screening saves lives but acknowledged the existence of overtreatment. Consequently, randomized trials were recommended to elucidate the appropriate treatment of screen-detected ductal carcinoma in situ (DCIS) and to gain a better understanding of its natural history. The LORIS trial will address these issues in low and low/intermediate grade screen detected (low risk) DCIS. Trial Design: LORIS is a phase III, multicentre, 2 arm study, with a built in 2 year feasibility phase, in women confirmed by central pathology review to have low risk DCIS. Comprehensive site training will be complimented by a patient friendly DVD designed to ensure consistent and appropriate use of terminology. Patients will be randomised between standard surgery and active monitoring with annual mammography. Follow-up will be for a minimum of 10 years. Eligibility Criteria: 1) Female, age ≥ 46 years 2) Screen-detected or incidental microcalcification (with no mass lesion clinically or on imaging) 3) Low risk DCIS on large volume vacuum-assisted biopsy, confirmed by central pathology review 4) Patient fit to undergo surgery 5) No previous breast cancer or DCIS diagnosis 6) Written informed consent Specific Aims: The LORIS Trial aims to establish whether patients with newly diagnosed low risk DCIS can safely avoid surgery without detriment to their wellbeing (psychological and physical) and whether those patients who do require surgery can be identified by pathological and radiological means. Primary endpoint: Ipsilateral invasive breast cancer free survival rate at 5 years Secondary endpoints: Overall survival; mastectomy rate; time to mastectomy; time to surgery; patient reported outcomes; health resource utilisation and assessment of predictive biomarkers. A digital image data repository and tissue bank will provide a prospective resource for both translational and imaging studies. Statistical Methods: A total of 932 patients will be randomized to a non-inferiority design to test the null hypothesis that active monitoring of women diagnosed with low risk DCIS is not non-inferior in terms of 5 year ipsilateral invasive breast cancer free survival (iiBCFS) rate compared to treatment with surgery. The iiBCFS rate will be compared across the two arms on a per protocol and intent-to-treat basis, using a 1-sided (α = 0.05) log-rank test for non-inferiority. The iiBCFS rate is assumed to be 97.5% in the surgery arm giving 80% power to exclude a difference of more than 2.5% in the active monitoring arm at 5 years. Present Accrual and Target Accrual: 20 UK sites have been identified to contribute to the feasibility phase of the trial. Enrolment of the first patient is expected in late 2013/early 2014. A further 40 sites will be recruited upon successful completion of the feasibility phase. For further information, please contact the LORIS Trial Office LORIS@trials.bham.ac.uk. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-3-01.

Radiotherapy after mastectomy for screen-detected ductal carcinoma in situ

BACKGROUND A role for radiotherapy after mastectomy for ductal carcinoma in situ (DCIS) is unclear. Using a prospective audit of DCIS detected through the NHS Breast Screening Programme we sought to determine a rationale for the use of post mastectomy radiotherapy for DCIS. METHODS Over a nine year period, from 9972 patients with screen-detected DCIS and complete surgical, pathology, radiotherapy and follow up data, 2944 women underwent mastectomy for DCIS of whom 33 (1.1%) received radiotherapy. RESULTS Use of post mastectomy radiotherapy was significantly associated with a close (<1 mm) pathology margin (χ(2)(1) 95.81; p < 0.00001), DCIS size (χ(2) (3) 16.96; p < 0.001) and the presence of microinvasion (χ(2)(1) 3.92; p < 0.05). At a median follow up 61 months, no woman who received radiotherapy had an ipsilateral further event, and only 1/33 women (3.0%) had a contralateral event. Of the women known not to have had radiotherapy post mastectomy, 45/2894 (1.6%) had an ipsilateral further event and 83 (2.9%) had a contralateral event. CONCLUSION Recurrence following mastectomy for DCIS is rare. A close (<1 mm) margin, large tumour size and microinvasion, may merit radiotherapy to reduce ipsilateral recurrence.

PRMT5 Is a Critical Regulator of Breast Cancer Stem Cell Function via Histone Methylation and FOXP1 Expression

Summary Breast cancer progression, treatment resistance, and relapse are thought to originate from a small population of tumor cells, breast cancer stem cells (BCSCs). Identification of factors critical for BCSC function is therefore vital for the development of therapies. Here, we identify the arginine methyltransferase PRMT5 as a key in vitro and in vivo regulator of BCSC proliferation and self-renewal and establish FOXP1, a winged helix/forkhead transcription factor, as a critical effector of PRMT5-induced BCSC function. Mechanistically, PRMT5 recruitment to the FOXP1 promoter facilitates H3R2me2s, SET1 recruitment, H3K4me3, and gene expression. Our findings are clinically significant, as PRMT5 depletion within established tumor xenografts or treatment of patient-derived BCSCs with a pre-clinical PRMT5 inhibitor substantially reduces BCSC numbers. Together, our findings highlight the importance of PRMT5 in BCSC maintenance and suggest that small-molecule inhibitors of PRMT5 or downstream targets could be an effective strategy eliminating this cancer-causing population.

Viewpoint: Availability of oestrogen receptor and HER2 status for the breast multidisciplinary meeting discussion; time to get it right

The efficacy and pivotal role of the multidisciplinary meeting (MDM) in informed decision making is well established. It aims to provide a forum in which clinical evidence combines with individual patient data to create a personalized treatment plan. It does not fulfil this role adequately when undertaken without the full results of the patients investigations being available. Neither doctor nor patient can make an informed decision about treatment options without knowledge of the tumour receptor status. Both targeted therapies and the aim to treat a majority of patients within clinical trials must now drive MDM decision making to be based on accuracy and best available treatment choices. A fully informed decision on treatment delayed by 1-2 weeks is clearly preferable to rushed time target-driven decisions made without the patient being offered a fully informed choice as ratified by a multidisciplinary team. Whilst the early anxiety of waiting for all relevant information to be available may be stressful for patients, not being sure that they have been offered fully informed treatment choices is also stressful and could cause longer lasting anxiety both during and after treatment. MDMs need to develop (along with targeted therapies) to retain their role as a forum whereby patients receive a correct, but specifically a full diagnosis and allow a fully informed discussion of all treatment options, including pre-operative clinical trials.