Real-world analysis of clinical and economic impact of 21-gene recurrence score (RS) testing in early-stage breast cancer (ESBC) in Ireland.

PURPOSE: Results from TAILOR-X suggest that up to 70% of hormone receptor-positive (HR+) node-negative (N0) ESBC patients (pts) may avoid chemotherapy (CT) with RS ≤ 25. We assess clinical and economic impacts of RS testing on treatment using real-world data. METHODS: From October 2011 to February 2019, a retrospective, cross-sectional observational study was conducted of HR+ N0 ESBC pts who had RS testing in Ireland. Pts were classified low risk (RS ≤ 25) and high risk (RS > 25). Clinical risk was calculated. Data were collected via electronic patient records. Cost data were supplied by the National Healthcare Pricing Regulatory Authority. RESULTS: 963 pts. Mean age is 56 years. Mean tumour size is 1.7 cm. 114 (11.8%), 635 (66%), 211 (22%), 3 (0.2%) pts had G1, G2, G3 and unknown G, respectively. 796 pts (82.8%) low RS, 159 (16.5%) high RS and 8 pts (0.7%) unknown RS. 263 pts (26%) were aged ≤ 50 at diagnosis; 117 (45%) had RS 0-15, 63 (24.5%) 16-20, 39 (15.3%) 21-25 and 40 (15.2%) RS 26-100. 4 pts (1.5%) had unknown RS. Post-RS testing, 602 pts (62.5%) had a change in CT decision; 593 changed to hormone therapy (HT) alone. In total, 262 pts received CT. Of pts receiving CT; 138 (53%) had RS > 25, 124 (47%) had RS ≤ 25. Of pts aged ≤ 50, 153 (58%) had high clinical risk, of whom 28 had RS 16-20. Assay use achieved a 62.5% change in treatment with 73% of pts avoiding CT. This resulted in savings of €4 million in treatment costs. Deducting assay costs, savings of €1.9 million were achieved. CONCLUSION: Over the 8 years of the study, a 62.5% reduction in CT use was achieved with savings of over €1,900,000.

Phenotypic analysis of familial breast cancer: comparison of BRCAx tumors with BRCA1-, BRCA2-carriers and non-familial breast cancer.

AIMS: Women with inherited pathogenic mutations in the BRCA1 or BRCA2 genes have up to an 85% risk of developing breast cancer in their lifetime. However, only about 20% of familial breast cancer is attributed to mutations in BRCA1 and BRCA2, while a further 5-10% are attributed to mutations in other rare susceptibility genes such as TP53, STK11, PTEN, ATM and CHEK2. Despite extensive efforts to explain the missing heritability of this disease, the majority of familial clustering in breast cancer remains largely unexplained. We aim to analyze the pathology of familial cases of which no pathogenic mutation is yet identified. METHODS: We compared the pathological phenotype of BRCA1/BRCA2 negative familial breast cancer (BRCAx) to BRCA1-positive, BRCA2-positive and sporadic cases without a family history. Age-adjusted analysis is summarized in odd's ratios and confidence intervals for tumor type, grade, lymph node, ER and HER2 status. RESULTS: We found non-familial cases to be more likely to be ER positive (P = 0.041) as compared with BRCAx tumors. More cases of lobular carcinoma were found with BRCAx as compared to BRCA1 tumors (P = 0.05). After multivariate logistic regression analysis, BRCAx tumors are more likely ER positive (P = 0.001) and HER2 positive (P = 0.047) in comparison to BRCA1. Conversely, BRCAx cases are less likely to be ER positive (P = 0.02) but more likely to be HER2 positive (P = 0.021) as compared with BRCA2 tumors. CONCLUSION: Our findings suggest that BRCA1, BRCA2 and BRCAx tumors differ in phenotype from non-familial and familial BRCA1-positive and BRCA2-positive tumors. Further studies will need to be performed in this important population in order to develop strategies for early detection and prevention.

Transcriptional regulation of cellular senescence.

Cellular senescence is an irreversible arrest of proliferation. It is activated when a cell encounters stress such as DNA damage, telomere shortening or oncogene activation. Like apoptosis, it impedes tumour progression and acts as a barrier that pre-neoplastic cells must overcome during their evolution toward the full tumourigenic state. This review focuses on the role of transcriptional regulators in the control of cellular senescence, explores how their function is perturbed in cancer and discusses the potential to harness this knowledge for future cancer therapies.

Rapid assessment breast clinics--evolution through audit.

This observational, cohort study aimed to examine the potential utility of Rapid Assessment Breast Clinics (RABC) beyond cancer detection at presentation. One thousand four hundred and twenty nine women were studied over an 18 month period. 154 (10.7%) had breast cancer - 87.7% of whom were seen expediently with 92.9% being diagnosed at one attendance. One hundred and forty three (10%) of those with a benign diagnosis were found by routine questioning to have significant familial risk separate to their reason for referral. Despite careful triage, considerable contamination of appointment allotment occurred with many who were correctly triaged as non-urgent being seen 'urgently'. One hundred and seventy six attendees (12.3%) had neither the symptom that triggered referral, nor breast lump, nipple discharge nor family history of breast cancer, while 283 (19.8%) had no objective clinical or radiological abnormality. Although RABC reliably categorise malignant versus non-malignant diagnoses despite cluttering by low risk women, a significant proportion of non-cancer patients still require address of future risk rather than reassurance of their present status alone.

Quality control in breast cancer surgery.

Quality assurance is the process by which quality care can be assessed. The general principles include setting a standard with the aim of achieving particular outcomes, followed by the evaluation of parameters that allow for quality assessment. Locoregional and survival outcomes are the major parameters but require years to evaluate and have other limitations. Other parameters therefore may assist in evaluation, such as the availability of the structures and processes required to achieve desired outcomes. Unlike chemotherapy and radiotherapy the quality of surgery is difficult to quantify, yet it is central to the issue of locoregional control and survival. In breast cancer surgery, quality control starts at the diagnostic service; from referral by the family practitioner to the appropriate triage of patients thereby preventing diagnostic delays. The surgical oncologist is pivotal in the multidisciplinary input necessary with both radiologists and pathologists in achieving the correct preoperative diagnoses of symptomatic and screen detected lesions as specified by many of the guidelines. Quality control of the operative surgery addresses issues such as training, volume and life audit of the surgeon. Standardisation of operative technique, pathology reporting with emphasis on specimen orientation and margins, management of the axilla and how it impacts on adjuvant treatment are other important issues. More recently, the availability of breast reconstruction services and the development of the oncoplastic surgeon is becoming an important quality issue. Finally, the quality of the follow up process provides the tools to assess the outcome of both the patient and the service.

Informing the public about advances in cancer therapy.

The word cancer continues to be associated with fear and pessimism among the general public, but they also hear of "new breakthroughs" in the field of oncology. This paper considers whether or not such research advances in cancer are occurring and, if so, is this information being accurately transmitted both within and outside the medical profession. If information is to be given to the public, what preparatory work needs to be achieved in order that this is done effectively.

Sentinel node biopsy for breast cancer may have little to offer four-node-samplers. results of a prospective comparison study.

The aims of the study were to determine how often four node axillary sampling (4NAS) encompasses the sentinel node (SN) and to compare the relative sensitivity of 4NAS with sentinel node biopsy (SNB) for axillary node staging. 200 patients with breast cancer were preoperatively injected with 27 MBq 99m-Tc-labelled colloid adjacent to the tumour. At operation, standard 4NAS was performed. Each node was counted ex vivo using a probe. A search was then made to find a node with higher counts in vivo directed by the probe. If found, it was excised. Each node was submitted separately to pathology. A SN was identified in 191 patients (96%). The SN was contained in the 4NAS in 153 patients (80%) and identified separately in 38 patients (20%). Of 60 node-positive patients, 49 were positive by 4NAS and SNB, the SN was not identified in 2 and in 8 the SN was falsely negative compared with 4NAS. For 1 patient, the SN was positive and the 4NAS negative. SNB performed using radiolabelled colloid has no advantage over 4NAS when nodes are assessed by standard histological technique.

Mammographic size of ductal carcinoma in situ does not predict the presence of an invasive focus.

A proportion of women thought to have ductal carcinoma in situ (DCIS) on mammography and a core biopsy showing DCIS only, in fact have an invasive focus on surgical excision. This study aims to identify the percentage of such patients who harbour an invasive focus and to ascertain features which can predict the presence of invasion. 140 patients had a core biopsy diagnosis of DCIS without invasion. All patients had their core biopsy graded and mammography was performed on 128 patients. Mammographic findings were classified by a radiologist blinded to the surgical findings into normal, mass/distortion or microcalcification. The extent of the microcalcifications was measured. The core biopsies were graded into high, intermediate or low grade DCIS groups. The core biopsy and radiological findings were compared to see if they could predict the presence of invasive disease at surgical excision. Of the 140 patients, 61 (44%) had an invasive focus. 8 (47%) of 17 patients with normal mammography had an invasive focus. 4 (36%) of 11 patients with a mammographic mass had evidence of invasion. Of the 100 patients with mammographic microcalcifications 48 (48%) had an invasive focus. In the 10 patients with low grade DCIS on core biopsy, 3 (30%) had an invasive focus. Comparative studies in patients with intermediate and high grade DCIS, were 7 of 18 (39%) and 51 of 112 (46%), respectively. Thus, 44% of women thought to have DCIS only on preoperative investigation had an invasive focus. In contrast to previous expressed opinions, neither mammography or grade were predictive. We have not identified any factor capable of predicting a higher likelihood of an invasive focus.

Predicting invasion in mammographically detected microcalcification.

AIM: To identify pre-operative factors which predict presence of invasive disease within mammographically detected malignant microcalcification. MATERIALS AND METHODS: A retrospective analysis was undertaken of 116 serial stereotactic core needle biopsies (SCNBs) performed on malignant mammographic calcification. Final surgical pathology was correlated with pre-operative features (clinical, radiological and core histology) in an attempt to predict the presence of an invasive component. RESULTS: Thirty-eight clusters contained invasive carcinoma. The sensitivity of SCNB for invasion was 55%. Clinical features, calcium morphology and cluster size were not shown to be predictive of invasive disease. Ductal carcinoma in situ (DCIS) of high grade on core histology and increasing number of calcifications were predictive of increased risk of invasion (high grade core biopsy DCIS and > 40 calcifications 48% invasive at surgical histology; high grade core biopsy DCIS and < 40 calcifications 15% invasive; non-high grade core biopsy DCIS 0% invasive). CONCLUSIONS: Identification of those clusters diagnosed as DCIS by percutaneous biopsy which are likely to harbour an invasive component is possible. It would seem reasonable to consider staging the axilla at therapeutic surgery in these patients.

Psychosocial dimensions of BRCA testing: an overshadowed issue.

Routine cancer susceptibility testing will soon be feasible in clinical practice. However, to date, this new technology has entailed many limitations, including potential adverse psychosocial consequences. Empirical studies examining these psychosocial aspects are strikingly scarce, especially in continental European countries. Are we prepared for managing the psychosocial problems that emerge from widespread introduction of this practice? Current research do not take into account cross-cultural variations in attitudes and reactions towards genetic testing. This paper points to the urgent need for obtaining a more accurate picture on the psychosocial aspects of breast cancer gene testing and disclosure in order to design recommendations for implementation in populations with highly variable cultural and legal background.

Attitudes towards intramural continuing medical education: a european perspective.

Continuing medical education (CME) is now one of the key areas of development in medical education. This paper describes the development of an intramural continuing medical education programme de novo in a newly opened cancer institute in Italy, which provided a unique opportunity to study attitudes towards the concepts and goals of continuing medical education as most of the individuals involved in this programme were exposed to continuing medical education for the first time. The continuing medical education programme was overseen by a CME committee for 1 year. Three 1-hour sessions were delivered each week and one credit point was awarded for each session. The sessions included grand rounds, clinical-based teaching and a 3-weekly rotating schedule of pathology, radiology and research. Participants were all the medical doctors attending the European Institute of Oncology. Attendance at greater than 50% of the total sessions available yearly qualified the individual for certification by the CME committee of the Institute. A questionnaire was circulated to all medical doctors at the Institute at the end of the academic year to assess attitudes to CME in general. Forty-six out of 84 questionnaires were returned. The majority of those involved in this CME intramural programme undertook self-directed CME activities and at least 50% had not previously attended either grand rounds or research seminars. Most felt that CME should not be mandatory but that its activities should be monitored. The greatest difficulty with CME was in its timing.

Sentinel node localization in primary melanoma: preoperative dynamic lymphoscintigraphy, intraoperative gamma probe, and vital dye guidance.

BACKGROUND: Sentinel node (SN) biopsy can be used to select patients with primary melanoma for therapeutic lymphadenectomy. The aim of the study was to assess the efficacy of 3 methods to locate the SN: preoperative dynamic lymphoscintigraphy, intraoperative patent blue dye (PBD), and gamma-detecting probe (GDP). METHODS: We studied 133 patients with cutaneous melanoma and clinically negative lymph nodes. Within 24 hours before surgery, colloid labeled with technetium 99m was injected intradermally around the site of the primary melanoma. The patients were studied before their operations by using dynamic lymphoscintigraphy. A total of 208 SNs were found in 164 lymph node basins. In addition, all the patients had PBD injected immediately before the surgical procedure. When the blue-stained node was identified intraoperatively, its radioactivity level was measured with the GDP. In the absence of blue coloration, the GDP was used to trace the SN. RESULTS: Of 208 SNs, 168 (80.8%) were identified in the regional draining basin during intraoperative lymphatic mapping by using PBD. By using the GDP method, 202 (97.1%) of 208 were identified (GDP vs PBD; P < .01). By combining the 2 methods, 206 (99%) of 208 SNs were detected. Of the 133 patients, 29 (21.8%) had pathologically positive SNs, and were subsequently subjected to regional lymphadenectomy. In 26 (89.7%) of 29 patients, the SN was the only node with metastasis. Three cases (10.3%) of recurrence in patients with microscopic SN metastasis and 7 cases (6.7%) of recurrence in patients without SN metastasis were found during a median follow-up of 566 days. CONCLUSIONS: Preoperative dynamic lymphoscintigraphy and intraoperative mapping with PBD and GDP offer simple and reliable methods of staging regional lymph nodes without subjecting every patient to a regional lymphadenectomy.

An elderly patient with advanced locoregional melanoma.

There is no consensus on the management of cancer in elderly patients and age per se should not be the sole factor in the decision-making process. We present a case of regional metastatic melanoma in an 83-year-old patient who received either untested or inadequate treatments. The general condition and stage of the disease, rather than chronological age alone, should be the determinant factor.

Continuing medical education by satellite: implications for oncology education.

The need for rapid dissemination of medical information is linked with the requirement for training and career grade doctors to be up-to-date with their knowledge. Over 220 sites in Europe receive EuroTransMed oncology programmes, during the academic terms. The non-profit foundation brings together expert panels, providing the latest evidence for best practice. Viewers are able to interact during the programme with the panel members using phone, fax, ISDN and e-mail. Increasing use of telematics has helped in the development of this important quality learning initiative for doctors in Europe, and addressed the continuing education need of oncology health professionals.

Sentinel node localization in primary melanoma: learning curve and results.

Ninety primary melanoma patients were studied to investigate the importance of adopting the simultaneous use of patent blue dye (PBD) and lymphoscintigraphy plus gamma detection probe to locate the sentinel node (SN). In total 135 SNs in 105 basins were visualized preoperatively under a gamma camera after lymphoscintigraphy. When a SN was identified intraoperatively, its radioactivity level and colour were verified and documented. Two of the SNs seen on lymphoscintigraphy were not found. Using PBD 78.52% of the SNs were identified; 95.5% were identified using the gamma detection probe. Using both methods together 98.5% of the SNs were detected. Twenty-two patients (24.4%) had pathologically positive SNs. The surgical learning curve was assessed for the two techniques. The learning curve associated with the methodology was important in finding the SN when using PBD associated with lymphoscintigraphy, but not when the gamma detection probe was used; we found a statistically significant reduction in the percentage of stained SNs found using PBD in the initial 14 SNs biopsied compared with the subsequent 121 nodes. This is important as not all institutions have access to a gamma probe. The time required to identify each SN was documented and analysed. The duration of the procedure was significantly shorter for stained SNs than for non-stained SNs, which support the use of both PBD and the gamma probe. In conclusion, SN biopsy should be performed by surgeons and nuclear medicine doctors in co-operation, both methods being adopted simultaneously to reduce the percentage of procedure failures.

A comparison of 14 and 12 gauge needles for core biopsy of suspicious mammographic calcification.

This study was carried out to compare the efficacy of 14 vs 12 G needles in stereotactic core biopsy of mammographic calcification. A consecutive series of 100 impalpable mammographic calcifications, without an associated mass and requiring stereotactic core biopsy were randomly allocated to either 14 G or 12 G needle sampling. All biopsies were performed using an upright stereotactic digital unit (Senovision GE) and a Bard automated biopsy gun. Core biopsy results were categorized as either normal, benign, atypical ductal hyperplasia, suspicious of ductal carcinoma in situ (DCIS), DCIS or invasive cancer. The radiographic calcification retrieval rates, complete and absolute sensitivity for malignancy of DCIS and DCIS with an invasive focus were obtained by comparison of core results with surgical histology. Radiographic calcification retrieval was achieved in 86% when using 14 G and 12 G needles. The absolute sensitivity and complete sensitivity for diagnosing DCIS were the same with 12 G and 14 G needles (72% versus 71% and 93% versus 94%, respectively). The use of 12 G needles does not appear to confer benefit over the use of 14 G needles in the diagnosis of mammographic calcification.

Does transforming growth factor beta 1 play a role in the pathogenesis of chronic allograft rejection?

To investigate the potential role of Transforming Growth Factor beta 1 (TGF beta 1) in the pathogenesis of chronic allograft rejection, we studied TGF beta 1 expression in a rat aortic allograft model. mRNA and protein expression of total and endogenously active TGF beta 1 were analysed in infra-renal orthotopic aortic syngeneic and allogeneic grafts and matched with the histological appearances of the grafts, 2, 4 and 12 weeks post-transplantation. Serum levels of TGF beta 1 were also measured. The level of TGF beta 1 m RNA and protein expression appeared highest 2 and 4 weeks following transplantation in both syngeneic and allogeneic grafts, with significantly elevated levels of mRNA expression in the 2 week allograft specimens. These time-points correlate histologically with maximal inflammatory cell infiltration of the grafts. By 12 weeks post-transplantation, TGF beta 1 mRNA expression is reduced in allogeneic grafts compared to syngeneic grafts. However, detectable levels of total and endogenously active TGF beta 1 protein levels in the allografts exceed those measured in the syngeneic grafts at this time point. These results demonstrate the complex expression pattern of this growth factor during the progression of chronic rejection and suggest an aetiological link between TGF beta 1 and the process of accelerated graft atherosclerosis.

Oesophageal cancer treatment: studies, strategies and facts.

Esophageal cancer is among the ten most frequent cancers in the world. Once diagnosis is established prognosis is poor with five-year survival rates below 10%. Over the last few years, the evidence--base for treatment of oesophageal cancer has changed with the publication of several important articles in this field. This article reviews these and other relevant publications with focus on current evidence which holds potential for an improvement in survival in oesophageal cancer patients. Prevention and early detection represent the mainstay in the ongoing struggle to improve prognosis, which is most stringently linked to tumor stage. Other efforts have been dedicated to optimise surgical treatment, radiotherapy and chemotherapy and to discover the most efficient combinations of these treatment modalities. Strong but not unanimous evidence in favour of a multimodality approach with chemoradiotherapy followed by surgery has accumulated in recent years, and confirmatory trials are presently ongoing. A pathological complete response to chemoradiotherapy has been identified to significantly enhance survival. Among the strategies to achieve higher response rates, variations in the administration of the most commonly used drugs rather than higher drug and radiation dosages seem promising. Occult lymphatic spread has been recognized as a major source of recurrence and has been successfully targeted by three field surgical dissection and extended field radiotherapy. In search of the optimal treatment for patients with oesophageal cancer, a variety of different tracks are being pursued. This review outlines and analyses current treatment approaches and investigates how recent advances may impact on patient management.