Spanish teachers in the USA are responsible for showing students what Spanish looks and sounds like (Ballman, Liskin-Gasparro & Mandell, 2001) and therefore act as role-models for their students in ...terms of their attitudes towards different varieties of Spanish. They must choose which features from which varieties to teach their students (Burns, 2018). Spanish teachers in the UK found Caribbean Spanish difficult to comprehend (Bárkányi & Fuerte Gutiérrez, 2019) and Spanish teachers in the USA preferred Peninsular Spanish over other varieties (Martínez-Franco, 2019), similar to Spanish teachers in Australia (Ortiz-Jiménez, 2019). The current study investigates (dis)preferences towards different regional varieties of Spanish by 63 primary, secondary and postsecondary teachers of Spanish in the USA. The findings indicate preferences split among four macro-varieties and a dispreference for Caribbean Spanish, highlighting the importance of comprehension and exposure to varieties regardless of prior explicit training on the topic.
Germline pathogenic variants mutations) in the BRCA1 and BRCA2 genes cause an increased risk of breast cancer and ovarian cancer. Mainstream cancer genetic testing (MCG) was introduced for breast ...cancer patients in our unit in 2013. Non-geneticist clinicians have been trained to offer genetic testing during initial treatment planning. We assessed the impact of timely test results on surgical decision-making.
Women who had undergone mainstream genetic testing for breast cancer between September 2013 and September 2018 were identified from a prospective database. Surgical data were collected retrospectively.
580 eligible women had mainstream genetic testing. For 474 this was their first breast cancer diagnosis. The median age was 46 years (interquartile range (IQR) 38–57). The indications were: age ≤45 years for 233 (49%); triple negative disease for 192 women (40.5%); bilateral breast cancer age <60 for 39 (8%) and other for 72 (14%) women. The median time for test initiation to result was 18 days (IQR 15-21). 302 (64% received results before surgery. 88% of those found to have a BRCA mutation before surgery opted for bilateral mastectomy (compared to 5% with BRCA wild type). An additional 106 patients had a new diagnosis on a background of previous treatment. Of these all with a pathogenic variant chose bilateral mastectomy.
Timely BRCA gene testing influences surgeons’ and patients’ choice of surgery. It reassures women with a negative result and allows those with a positive result to take an active decision about the management of their future risk.
•Early access to rapid genetic testing for high risk women allows results to contribute to surgical decision-making.•Median time to receiving results was 29 calendar days9% had a pathogenic mutation.•Women with mutations were more likely to have bilateral mastectomy as their primary surgery if results were available before surgery. Those for whom results were available after surgery often chose additional risk-reducing surgery.•Only 4% of women without a mutation had bilateral mastectomy.
Hormonal therapy is used as a treatment option in high-grade ovarian carcinoma (HGOC), but the role and choice of treatment remains unclear. Agents used include tamoxifen and aromatase inhibitors. ...Our aim was to evaluate the efficacy of tamoxifen (T) and letrozole (L) in HGOC in clinical practice and investigate factors influencing clinical outcome.
A retrospective review of patients with relapsed HGOC treated with either tamoxifen or letrozole at the Royal Marsden Hospital between 2007 and 2012 was performed. The primary endpoint of the study was objective response rate (ORR). Secondary endpoints included CA125 response, clinical benefit rate (CBR) and duration of response. Platinum-sensitivity and ER-status were evaluated as predictors of treatment response.
97 patients were included (43 T, 54 L); median age 63 years (20-92); 91% high-grade serous; median number of lines of prior chemotherapy 3 (1-8); 60% platinum-resistant, 40% platinum-sensitive; 52% ER + ve, 1% ER-ve, 47% unknown. 14 patients (6 T, 8 L) achieved a partial response, with ORR (RECIST) of 14% (T) and 15% (L). The CBR for ≥3 months was 65% (22/43) for tamoxifen and 56% (22/54) for letrozole. There was no significant difference in ORR (p = 0.99) or CBR (p = 0.14) between tamoxifen and letrozole. 22 patients (23%) had a CA-125 response with hormonal therapy (10 T - 23% and 12 L - 22%). ORR did not differ by platinum sensitivity (p = 0.42); or ER-status (positive vs unknown, p = 0.12). Responders to letrozole had longer durations of response than responders to tamoxifen (26 vs 11.5 months, p = 0.03), but equivalent disease stability duration (9.6 vs 7.2 months respectively, p = 0.11).
Within the constraints of a retrospective study, we identified that patients treated with letrozole had a significantly longer duration of response than those treated with tamoxifen. Treatment with either tamoxifen or letrozole is a rational treatment option for patients with ER + ve HGOC, with equivalent ORR, CBR and disease stability.
Abstract Objectives To evaluate the long-term cost-effectiveness of germline BRCA1 and BRCA2 (collectively termed “BRCA”) testing in women with epithelial ovarian cancer, and testing for the relevant ...mutation in first- and second-degree relatives of BRCA mutation–positive individuals, compared with no testing. Female BRCA mutation–positive relatives of patients with ovarian cancer could undergo risk-reducing mastectomy and/or bilateral salpingo-oophorectomy. Methods A cost-effectiveness model was developed that included the risks of breast and ovarian cancer; the costs, utilities, and effects of risk-reducing surgery on cancer rates; and the costs, utilities, and mortality rates associated with cancer. Results BRCA testing of all women with epithelial ovarian cancer each year is cost-effective at a UK willingness-to-pay threshold of £20,000/quality-adjusted life-year (QALY) compared with no testing, with an incremental cost-effectiveness ratio of £4,339/QALY. The result was primarily driven by fewer cases of breast cancer (142) and ovarian cancer (141) and associated reductions in mortality (77 fewer deaths) in relatives over the subsequent 50 years. Sensitivity analyses showed that the results were robust to variations in the input parameters. Probabilistic sensitivity analysis showed that the probability of germline BRCA mutation testing being cost-effective at a threshold of £20,000/QALY was 99.9%. Conclusions Implementing germline BRCA testing in all patients with ovarian cancer would be cost-effective in the United Kingdom. The consequent reduction in future cases of breast and ovarian cancer in relatives of mutation–positive individuals would ease the burden of cancer treatments in subsequent years and result in significantly better outcomes and reduced mortality rates for these individuals.
Despite the increasing clinical importance of germline BRCA mutation status in managing women with ovarian cancer, few patients are currently being tested. The traditional means of selecting patients ...for BRCA mutation testing using restrictive criteria will miss many women with a mutation. To expand access to testing and streamline the testing process, several centres in the UK have been developing new models for BRCA testing. Trials with these integrated models involving closer collaborations between genetics and oncology services are now under way. In addition to testing for BRCA mutations, there is also increasing interest in testing for other genes associated with a predisposition to ovarian cancer. Advances in next-generation sequencing technology have resulted in the development of comprehensive genetic testing panels for use in the research and diagnostic settings. Interest is also increasing in expanding testing for somatic mutations in ovarian cancer, particularly for genes such as BRCA1 and BRCA2, whereby mutations may allow more patients to benefit from targeted agents, including poly(ADP-ribose) polymerase inhibitors. In this review, the issues of who should be offered testing, how testing could be delivered, when testing should occur and the technology and costs associated with genetic testing are addressed.
Adolescents and young adults (AYAs) diagnosed with cancer between ages 15–39 years may harbour germline variants associated with cancer predisposition. Such variants represent putative therapeutic ...targets, as may somatic variants in the tumour. Germline and tumour molecular profiling is increasingly utilised to facilitate personalisation of cancer treatment in such individuals.
Considering AYAs with advanced solid tumours managed in a specialist drug development unit (DDU), the aims of this study were to investigate the use and impact of:
1. Germline genetic assessment.
2. Tumour molecular profiling.
AYAs treated in the DDU at the Royal Marsden Hospital between 2002 and 2016 were identified from departmental databases. Data regarding clinicopathological features, clinical assessments and germline and tumour genetic testing were retrieved by chart review.
The study cohort included 219 AYAs. Common cancer types included sarcoma (41, 19%); cervical (27, 12%); breast (25, 11%); ovarian (23, 11%) and colorectal (21, 10%) cancers. Germline testing was undertaken in 34 (16%) patients, 22 of whom carried a pathogenic variant. Using current testing criteria, an additional 32 (15%) would be eligible for germline testing based on their personal history of cancer alone. Tumour testing was undertaken in 46 (21%) individuals. Somatic mutations were commonly identified in TP53 13 (28%); PIK3CA (8, 18%); KRAS (4, 9%) and MET 5 (11%).
A significant proportion of AYAs with advanced cancer have targetable somatic or germline mutations. Consideration of familial risk factors and inclusion of germline testing wherever appropriate can complement tumour testing to optimise patient management and inform management of at-risk relatives.
•Adolescents/young adults with cancer may have a germline cancer predisposition.•Some AYAs should have germline genetic testing, even in absence of family history.•Documentation of family history of AYAs with cancer is unsatisfactory.•Tumour-based genetic testing may identify clinically targetable mutations.•Larger multi-gene panels increase uncertainty as well as diagnostic yield.
The NHS Breast screening programme has provided surveillance to women at high-risk of breast cancer since 2013. High-risk women with germline mutations were surveyed one and three years ...post-repatriation to assess screening. The majority received appropriate screening according to clinical recommendations.
Since April 2013, the UK’s National Health Service Breast Screening Programme (NHSBSP) centers have been obliged to provide services for women at the highest risk of breast cancer, including those carrying highly penetrant single gene mutations (BRCA1, BRCA2, TP53). Since then, such individuals previously undergoing surveillance in the Royal Marsden Hospital were referred to their local NHSBSP centers. We aimed to assess patient experience of surveillance provided by local NHSBSP services at 1 and 3 years after repatriation.
High-risk gene mutation carriers referred to the NHSBSP for breast cancer surveillance were identified from a departmental database in the Cancer Genetics Unit and invited to complete questionnaires about their experience of surveillance under this new pathway, first in 2014 and again in 2016.
Three hundred forty-six individuals were invited to participate in 2014, of whom 182 responded (53%). A total of 464 patients were invited in 2016, of whom 246 (53%) completed the second questionnaire. Ninety-four percent of patients with residual breast tissue received some screening at the first (n = 161) and second (n = 185) time points. Ninety-one percent of patients (n = 146) received at least recommended surveillance in the year preceding the initial survey, a proportion decreasing slightly by the second time point (n = 164, 87%). Seventeen percent of individuals required additional diagnostic investigations, with cancers detected in 2%. These proportions remained stable between surveys.
Repatriation of high-risk individuals from Royal Marsden Hospital to NHSBSP centers has been successfully accomplished. Most individuals received appropriate recommended annual surveillance. Further improvements are required to ensure equal and timely provision of recommended surveillance.
Molecular aberrations in cancer may represent therapeutic targets, and, if arising from the germline, may impact further cancer risk management in patients and their blood relatives. Annually, ...600–700 patients are referred for consideration of experimental drug trials in the Drug Development Unit (DDU) in our institution. A proportion of patients may merit germline genetic testing because of suspicious personal/family history or findings of tumour-based testing. We aimed to assess the impact of different multidisciplinary interventions on family history taking and referral rates from DDU to Cancer Genetics Unit (CGU).
Over 42 months, three interventions were undertaken at different intervals: (1) embedding a genetics provider in the DDU review clinic, (2) ‘traffic light’ system flagging cancers with a heritable component and (3) virtual multidisciplinary meeting (MDM). Comparative analyses between intervals were undertaken, including referral rates to CGU, investigations and patient outcomes. Family history taking in a sample of 20 patients managed in each interval was assessed by a retrospective chart review.
Frequency of family history taking and referral to CGU, increased with each intervention, particularly, the virtual MDM (40% vs 85%). Referral rates increased over the study period, from 0.1 referral/week (5/year, 0.36% total referrals) to 1.2/week (projected 63/year, 3.81%). Forty-four (52%) patients referred required germline testing; in three of whom, variants were identified. Non-attendance rates were low (6, 7%).
Patients in the DDU are unique, with long cancer histories and often short estimated life expectancy. Multidisciplinary working between CGU and DDU facilitates germline testing of those patients who may otherwise miss the opportunity.
•Criteria for germ line genetic testing change over time.•Patients with advanced cancer may miss the opportunity for genetic testing.•We propose three interventions to improve rates of referral for genetic counselling.•The study cohort includes patients with advanced metastatic cancer.•Referral rates and family history documentation improved with each intervention.
Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease caused by inherited or de novo germline pathogenic variants in TP53. Individuals with LFS have a 70-100% lifetime risk of developing ...cancer. The current standard of care involves annual surveillance with whole-body and brain MRI (WB-MRI) and clinical review; however, there are no chemoprevention agents licensed for individuals with LFS. Preclinical studies in LFS murine models show that the anti-diabetic drug metformin is chemopreventive and, in a pilot intervention trial, short-term use of metformin was well-tolerated in adults with LFS. However, metformin's mechanism of anticancer activity in this context is unclear.
Metformin in adults with Li-Fraumeni syndrome (MILI) is a Precision-Prevention phase II open-labelled unblinded randomised clinical trial in which 224 adults aged ≥ 16 years with LFS are randomised 1:1 to oral metformin (up to 2 mg daily) plus annual MRI surveillance or annual MRI surveillance alone for up to 5 years. The primary endpoint is to compare cumulative cancer-free survival up to 5 years (60 months) from randomisation between the intervention (metformin) and control (no metformin) arms. Secondary endpoints include a comparison of cumulative tumour-free survival at 5 years, overall survival at 5 years and clinical characteristics of emerging cancers between trial arms. Safety, toxicity and acceptability of metformin; impact of metformin on quality of life; and impact of baseline lifestyle risk factors on cancer incidence will be assessed. Exploratory end-points will evaluate the mechanism of action of metformin as a cancer preventative, identify biomarkers of response or carcinogenesis and assess WB-MRI performance as a diagnostic tool for detecting cancers in participants with LFS by assessing yield and diagnostic accuracy of WB-MRI.
Alongside a parallel MILI study being conducted by collaborators at the National Cancer Institute (NCI), MILI is the first prevention trial to be conducted in this high-risk group. The MILI study provides a unique opportunity to evaluate the efficacy of metformin as a chemopreventive alongside exploring its mechanism of anticancer action and the biological process of mutated P53-driven tumourigenesis.
ISRCTN16699730. Registered on 28 November 2022. URL: https://www.isrctn.com/ EudraCT/CTIS number 2022-000165-41.
Adolescent and young adult (AYA) patients with advanced solid tumours are often considered for phase I clinical trials with novel agents. The outcome of AYAs in these trials have not been described ...before.
To study the outcome of AYA patients in phase I clinical trials.
Clinical trial data of AYAs (defined as aged 15–39 years at diagnosis) treated at the Drug Development Unit, Royal Marsden Hospital, between 2002 and 2016, were analysed.
From a prospectively maintained database of 2631 patients treated in phase I trials, 219 AYA patients (8%) were identified. Major tumour types included gynaecological cancer (25%) and sarcoma (18%). Twenty-five (11%) had a known hereditary cancer syndrome (most commonly BRCA). Molecular characterisation of tumours (n = 45) identified mutations most commonly in TP53 (33%), PI3KCA (18%) and KRAS (9%). Therapeutic targets of trials included DNA damage repair (16%), phosphoinositide 3-kinase (PI3K) (16%) and angiogenesis (16%). Grade 3/4 toxicities were experienced in 26% of patients. Of the 214 evaluable patients, objective response rate was 12%, with clinical benefit rate at 6 months of 22%. Median overall survival (OS) was 7.5 months (95% confidence interval: 6.3–9.5), and 2-year OS was 11%. Of patients with responses, 36% were matched to phase I trials based on germline or somatic genetic aberrations.
We describe the outcome of the largest cohort of AYA patients treated in phase I trials. A subgroup of these patients demonstrates benefit, with several durable responses beyond 2 years. A sizeable proportion of AYA patients have cancer syndromes, significant family history or somatic molecular aberrancies which may influence novel therapeutic treatment options.
•Outcomes of the largest cohort of adolescents and young adults (AYAs) in phase I clinical trials reported.•Durable responses and prolonged survival described in a subgroup of patients.•Several AYA cancer patients have cancer syndromes or somatic genetic aberrancies.
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