Terri P. McVeigh

The impact of Oncotype DX testing on breast cancer management and chemotherapy prescribing patterns in a tertiary referral centre

Introduction The use of chemotherapy in node-negative, (O)Estrogen Receptor (ER)-positive breast cancer has changed significantly since the introduction of Oncotype DX to determine systemic recurrence risk based on tumour genomic signature. Aims This study aims to1. Document longitudinal changes in chemotherapy use,2. Assess the impact of new evidence on local protocol. Methods A cohort study was undertaken, including consecutive patients with early node-negative, ER-positive breast cancer diagnosed between 2006 and May 2013, including a period of prospective clinical trial (Trial Assigning Individualised Options for Treatment (TAILORx)) recruitment. Data were collected regarding patient demographics, tumour clinico-pathological features, Oncotype DX use and recurrence score and chemotherapy use. All therapeutic decisions were made following multidisciplinary discussion, with adherence to guidelines and consideration of trial protocol and Oncotype DX recurrence scores. Results 479 consecutive patients were included in the study, of whom 241 (50%) underwent Oncotype DX testing, 97 as part of the TAILORx clinical trial. Oncotype DX testing began on a trial basis in 2007 and until October 2011, only patients enrolled on TAILORx availed of genomic profiling. From October 2011, Oncotype DX was used in all eligible patients as per National Cancer Control Programme (NCCP) guidelines. A total of 216 (45%) patients received chemotherapy. The use of chemotherapy changed in inverse proportion to the availability of the genomic assay. Of those patients in whom Oncotype DX was utilised, 138 (57%) were spared chemotherapy. Conclusion This study validates the use of molecular testing in the rationalisation of systemic therapy.

Increasing Reporting of Adverse Events to Improve the Educational Value of the Morbidity and Mortality Conference

BACKGROUND The aim of this study was to investigate the impact of a validated complication proforma on surgical Morbidity and Mortality (M&M) conference reporting. STUDY DESIGN The ACS-NSQIP (American College of Surgeons-National Surgical Quality Improvement Program) 30-day complication proforma, when implemented, previously showed a 25% increase in morbidity and a 50% increase in mortality reporting. A pilot study introducing the paper-based proforma was undertaken, collecting prospective M&M data for 2,094 of 2,209 colorectal, upper gastrointestinal, breast, and vascular inpatients (94.7% compliance). A comparative analysis using the proforma vs traditional M&M data collection was used to compare accuracy of M&M data reporting. RESULTS There was a 73% increase in morbidities reported using the proforma as compared with M&M reporting (547 vs 316), and an increase of 10.81% (37 vs 41) in the reporting of mortalities. Of those patients with morbidities (n = 278), 70.24% (n = 203) had at least 1 surgical intervention. The median length of stay in patients with morbidities was 12 vs 3 days in those with no morbidities. CONCLUSIONS We demonstrated that prospective standardized incident recording provides significantly more accurate assessment of M&M data compared with current reporting methods. This increased accuracy should favorably affect surgical performance indicators and casemix funding.

The KRAS-Variant Is Associated with Risk of Developing Double Primary Breast and Ovarian Cancer

Purpose A germline microRNA binding site-disrupting variant, the KRAS-variant (rs61764370), is associated with an increased risk of developing several cancers. Because this variant is most strongly associated with ovarian cancer risk in patients from hereditary breast and ovarian families (HBOC), and with the risk of premenopausal triple negative breast cancer, we evaluated the association of the KRAS-variant with women with personal histories of both breast and ovarian cancer, referred to as double primary patients. Experimental Design Germline DNA from double primary patients was tested for the KRAS-variant (n = 232). Confirmation of pathologic diagnoses, age of diagnoses, interval between ovarian cancer diagnosis and sample collection, additional cancer diagnoses, and family history were obtained when available. All patients were tested for deleterious BRCA mutations. Results The KRAS-variant was significantly enriched in uninformative (BRCA negative) double primary patients, being found in 39% of patients accrued within two years of their ovarian cancer diagnosis. Furthermore, the KRAS-variant was found in 35% of uninformative double primary patients diagnosed with ovarian cancer post-menopausally, and was significantly associated with uninformative double primary patients with a positive family history. The KRAS-variant was also significantly enriched in uninformative patients who developed more then two primary cancers, being found in 48% of women with two breast primaries plus ovarian cancer or with triple primary cancers. Conclusions These findings further validate the importance of the KRAS-variant in breast and ovarian cancer risk, and support the association of this variant as a genetic marker for HBOC families previously considered uninformative.

Assessing the impact of an ageing population on complication rates and in-patient length of stay

BACKGROUND Ireland has an ageing population; with the proportion of people aged over 80 years estimated to increase over the next 20 years from 1.1% to 2.1%. AIMS The aim of this study was to examine the demographics of the population served by the surgical department in a tertiary referral centre in the west of Ireland and to examine whether increasing age had an influence on morbidity, mortality and length of stay. METHODS Data pertaining to all surgical admissions over a 6-month period between was collected prospectively using an ACS-NSQIP based proforma. Data collected included patient age, gender, operative intervention, in-patient length of stay, mode of admission and complications related to their admission. RESULTS A total of 2209 patients were admitted under the care of the general, vascular and breast services in our centre over a 6-month period between August and January. Two thousand and nineteen patients had complete data collected. The average age was 50.37 years (± 23.62), with 24.12% (n = 533) older than 70 years. Only 12.31% of patients aged younger than 70 years experienced morbidity, compared to 25.10% of older patients. It was shown that there was a stepwise increase with complication rates and hospital in-patient stay across each decade of increasing age. Multivariate analysis showed those factors most predictive of a complication to include emergency admission, major or complex major surgical intervention, female gender and age. Length of stay was also found to have a positive correlation with increasing age (Spearmans Rho, p < 0.001). CONCLUSION Increasing age is associated with increased complication rates and increased hospital length of stay.

Clinical use of the Oncotype DX genomic test to guide treatment decisions for patients with invasive breast cancer

Implementation of the Oncotype DX assay has led to a change in the manner in which chemotherapy is utilized in patients with early stage, estrogen receptor (ER)-positive, node-negative breast cancer; ensuring that patients at highest risk of recurrence are prescribed systemic treatment, while at the same time sparing low-risk patients potential adverse events from therapy unlikely to influence their survival. This test generates a recurrence score between 0 and 100, which correlates with probability of distant disease recurrence. Patients with low-risk recurrence scores (0–17) are unlikely to derive significant survival benefit with adjuvant chemotherapy and hormonal agents derived from using adjuvant hormonal therapy only. Conversely, adjuvant chemotherapy has been shown to significantly improve survival in patients with high-risk recurrence scores (≥31). Trials are ongoing to determine how best to manage patients with recurrence scores in the intermediate range. This review outlines the introduction and impact of Oncotype DX testing on practice; ongoing clinical trials investigating its utility; and challenging clinical scenarios where the absolute recurrence score may require careful interpretation. We also performed a bibliometric analysis of publications on the topics of breast cancer and Oncotype DX as a surrogate marker of acceptability and incorporation of the assay into the management of patients with breast cancer.

Lobular Breast Cancer in a CDH1 Splice Site Mutation Carrier: Case Report and Review of the Literature

Abstract: Introduction: We present the case of a 49 year old female treated for an invasive lobular carcinoma, on a background of a proven CDH1 gene mutation for which she had previously undergone a prophylactic gastrectomy. Aim: CDH1 mutations are known to predispose affected individuals to diffuse gastric cancer and other cancers. We aim to outline the role of CDH1 in breast cancer, and to investigate current guidelines in management and screening of mutation carriers. Methods: A Medline and Scopus search was carried out to identify articles with respect to CDH1 and breast cancer. Manual scanning of articles arising from this search was carried out and irrelevant articles exluded. Results: CDH1 mutations act to alter the function of E-cadherin. Loss of E-cadherin expression is characteristic of lobular breast cancers. The penetrance of lobular breast cancers in female CDH1 mutation carriers is variable. CDH1 nonsense and frameshift mutations have been identified in sporadic cases. Breast cancer associated mutations have been found to cluster at the 3` end of CDH1. Screening in this cohort is difficult because of the radiolucent nature of lobular subtype of breast cancer. Prophylactic surgery is controversial given variability in penetrance. Conclusion: Female patients with CDH1 mutations should be offered, at minimum, annual surveillance with breast MRI. Consideration should be given towards surgical prophylaxis, or to pharmaceutical prophylaxis with oestrogen-based therapies.

Changing practices in the surgical management of hyperparathyroidism – A 10-year review

AIM Parathyroid surgery has undergone a paradigm shift over the last decade, with a move from traditional bilateral neck exploration to minimally invasive parathyroidectomy (MIP), and increasing reliance on pre- and intra-operative localization of overactive glands. We aimed to assess changing surgical practices and their impact on the management of parathyroid disease in a tertiary referral centre in the West of Ireland. METHODS A retrospective cohort analysis of those patients undergoing a surgical intervention for parathyroid disease in the period between 1999 and 2009 in our centre was carried out. Data was analysed using PASW (v18) software. RESULTS 248 procedures were performed, increasing from an annual rate of 6 in 1999 to 45 in 2009. 129 procedures were completed by minimally invasive means, following the introduction of MIP in 2003. Single-gland disease accounted for 87% of cases (n = 216) with carcinomas in 2 patients (0.8%). Pre-operative localization had disappointing diagnostic value, with high false negative rates for both ultrasound (37.3%) and Sestamibi Scanning (35.81%). Intra-operative adjuncts were more helpful, with intra-operative Parathyroid hormone monitoring facilitating curative resection of adenomas in 94.03% at 10 min. Median length of post-operative stay has significantly decreased from 6 days in 1999 to 1 night only in 2009 (p < 0.01, ANOVA). Those patients undergoing MIP had shorter stay than the open group (1.71 days -v-4.73, p = 0.003,t-test). CONCLUSION The practice in our centre has shifted to a less invasive approach. Increased utilisation of intra-operative adjuncts has facilitated this change, and resulted in favourable changes in length of stay, extent of dissection, and number of patients treated.

Screening for mismatch repair deficiency in colorectal cancer: data from three academic medical centers

Reflex immunohistochemistry (rIHC) for mismatch repair (MMR) protein expression can be used as a screening tool to detect Lynch Syndrome (LS). Increasingly the mismatch repair‐deficient (dMMR) phenotype has therapeutic implications. We investigated the pattern and consequence of testing for dMMR in three Irish Cancer Centres (CCs). CRC databases were analyzed from January 2005–December 2013. CC1 performs IHC upon physician request, CC2 implemented rIHC in November 2008, and CC3 has been performing rIHC since 2004. The number of eligible patients referred to clinical genetic services (CGS), and the number of LS patients per center was determined. 3906 patients were included over a 9‐year period. dMMR CRCs were found in 32/153 (21%) of patients at CC1 and 55/536 (10%) at CC2, accounting for 3% and 5% of the CRC population, respectively. At CC3, 182/1737 patients (10%) had dMMR CRCs (P < 0.001). Additional testing for the BRAF V600E mutation, was performed in 49 patients at CC3 prior to CGS referral, of which 29 were positive and considered sporadic CRC. Referrals to CGS were made in 66%, 33%, and 30% of eligible patients at CC1, CC2, and CC3, respectively. LS accounted for CRC in eight patients (0.8%) at CC1, eight patients (0.7%) at CC2, and 20 patients (1.2%) at CC3. Cascade testing of patients with dMMR CRC was not completed in 56%. Universal screening increases the detection of dMMR tumors and LS kindreds. Successful implementation of this approach requires adequate resources for appropriate downstream management of these patients.

Estrogen withdrawal, increased breast cancer risk and the KRAS-variant

The KRAS-variant is a biologically functional, microRNA binding site variant, which predicts increased cancer risk especially for women. Because external exposures, such as chemotherapy, differentially impact the effect of this mutation, we evaluated the association of estrogen exposures, breast cancer (BC) risk and tumor biology in women with the KRAS-variant. Women with BC (n = 1712), the subset with the KRAS-variant (n = 286) and KRAS-variant unaffected controls (n = 80) were evaluated, and hormonal exposures, KRAS-variant status, and pathology were compared. The impact of estrogen withdrawal on transformation of isogenic normal breast cell lines with or without the KRAS-variant was studied. Finally, the association and presentation characteristics of the KRAS-variant and multiple primary breast cancer (MPBC) were evaluated. KRAS-variant BC patients were more likely to have ovarian removal pre-BC diagnosis than non-variant BC patients (p = 0.033). In addition, KRAS-variant BC patients also appeared to have a lower estrogen state than KRAS-variant unaffected controls, with a lower BMI (P < 0.001). Finally, hormone replacement therapy (HRT) discontinuation in KRAS-variant patients was associated with a diagnosis of triple negative BC (P < 0.001). Biologically confirming our clinical findings, acute estrogen withdrawal led to oncogenic transformation in KRAS-variant positive isogenic cell lines. Finally, KRAS-variant BC patients had greater than an 11-fold increased risk of presenting with MPBC compared to non-variant patients (45.39% vs 6.78%, OR 11.44 [3.42–37.87], P < 0.001). Thus, estrogen withdrawal and a low estrogen state appear to increase BC risk and to predict aggressive tumor biology in women with the KRAS-variant, who are also significantly more likely to present with multiple primary breast cancer.

A germline mutation in the BRCA1 3’UTR predicts Stage IV breast cancer

BackgroundA germline, variant in the BRCA1 3’UTR (rs8176318) was previously shown to predict breast and ovarian cancer risk in women from high-risk families, as well as increased risk of triple negative breast cancer. Here, we tested the hypothesis that this variant predicts tumor biology, like other 3’UTR mutations in cancer.MethodsThe impact of the BRCA1-3’UTR-variant on BRCA1 gene expression, and altered response to external stimuli was tested in vitro using a luciferase reporter assay. Gene expression was further tested in vivo by immunoflourescence staining on breast tumor tissue, comparing triple negative patient samples with the variant (TG or TT) or non-variant (GG) BRCA1 3’UTR. To determine the significance of the variant on clinically relevant endpoints, a comprehensive collection of West-Irish breast cancer patients were tested for the variant. Finally, an association of the variant with breast screening clinical phenotypes was evaluated using a cohort of women from the High Risk Breast Program at the University of Vermont.ResultsLuciferase reporters with the BRCA1-3’UTR-variant (T allele) displayed significantly lower gene expression, as well as altered response to external hormonal stimuli, compared to the non-variant 3’UTR (G allele) in breast cancer cell lines. This was confirmed clinically by the finding of reduced BRCA1 gene expression in triple negative samples from patients carrying the homozygous TT variant, compared to non-variant patients. The BRCA1-3’UTR-variant (TG or TT) also associated with a modest increased risk for developing breast cancer in the West-Irish cohort (OR = 1.4, 95% CI 1.1-1.8, p = 0.033). More importantly, patients with the BRCA1-3’UTR-variant had a 4-fold increased risk of presenting with Stage IV disease (p = 0.018, OR = 3.37, 95% CI 1.3-11.0). Supporting that this finding is due to tumor biology, and not difficulty screening, obese women with the BRCA1-3’UTR-variant had significantly less dense breasts (p = 0.0398) in the Vermont cohort.ConclusionA variant in the 3’UTR of BRCA1 is functional, leading to decreased BRCA1 expression, modest increased breast cancer risk, and most importantly, presentation with stage IV breast cancer, likely due to aggressive tumor biology.