Lasofoxifene versus fulvestrant for ER+/HER2- metastatic breast cancer with an ESR1 mutation: results from the randomized, phase II ELAINE 1 trial.

BACKGROUND: Acquired estrogen receptor alpha (ER/ESR1) mutations commonly cause endocrine resistance in ER+ metastatic breast cancer (mBC). Lasofoxifene, a novel selective ER modulator, stabilizes an antagonist conformation of wild-type and ESR1-mutated ER-ligand binding domains, and has antitumor activity in ESR1-mutated xenografts. PATIENTS AND METHODS: In this open-label, randomized, phase II, multicenter, ELAINE 1 study (NCT03781063), we randomized women with ESR1-mutated, ER+/human epidermal growth factor receptor 2 negative (HER2-) mBC that had progressed on an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to oral lasofoxifene 5 mg daily or IM fulvestrant 500 mg (days 1, 15, and 29, and then every 4 weeks) until disease progression/toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were safety/tolerability. RESULTS: A total of 103 patients received lasofoxifene (n = 52) or fulvestrant (n = 51). The most current efficacy analysis showed that lasofoxifene did not significantly prolong median PFS compared with fulvestrant: 24.2 weeks (∼5.6 months) versus 16.2 weeks (∼3.7 months; P = 0.138); hazard ratio 0.699 (95% confidence interval 0.434-1.125). However, PFS and other clinical endpoints numerically favored lasofoxifene: clinical benefit rate (36.5% versus 21.6%; P = 0.117), objective response rate [13.2% (including a complete response in one lasofoxifene-treated patient) versus 2.9%; P = 0.124], and 6-month (53.4% versus 37.9%) and 12-month (30.7% versus 14.1%) PFS rates. Most common treatment-emergent adverse events with lasofoxifene were nausea, fatigue, arthralgia, and hot flushes. One death occurred in the fulvestrant arm. Circulating tumor DNA ESR1 mutant allele fraction (MAF) decreased from baseline to week 8 in 82.9% of evaluable lasofoxifene-treated versus 61.5% of fulvestrant-treated patients. CONCLUSIONS: Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation.

Quantifying T2-FLAIR Mismatch Using Geographically Weighted Regression and Predicting Molecular Status in Lower-Grade Gliomas.

BACKGROUND AND PURPOSE: The T2-FLAIR mismatch sign is a validated imaging sign of isocitrate dehydrogenase-mutant 1p/19q noncodeleted gliomas. It is identified by radiologists through visual inspection of preoperative MR imaging scans and has been shown to identify isocitrate dehydrogenase-mutant 1p/19q noncodeleted gliomas with a high positive predictive value. We have developed an approach to quantify the T2-FLAIR mismatch signature and use it to predict the molecular status of lower-grade gliomas. MATERIALS AND METHODS: We used multiparametric MR imaging scans and segmentation labels of 108 preoperative lower-grade glioma tumors from The Cancer Imaging Archive. Clinical information and T2-FLAIR mismatch sign labels were obtained from supplementary material of relevant publications. We adopted an objective analytic approach to estimate this sign through a geographically weighted regression and used the residuals for each case to construct a probability density function (serving as a residual signature). These functions were then analyzed using an appropriate statistical framework. RESULTS: We observed statistically significant (P value = .05) differences between the averages of residual signatures for an isocitrate dehydrogenase-mutant 1p/19q noncodeleted class of tumors versus other categories. Our classifier predicts these cases with area under the curve of 0.98 and high specificity and sensitivity. It also predicts the T2-FLAIR mismatch sign within these cases with an under the curve of 0.93. CONCLUSIONS: On the basis of this retrospective study, we show that geographically weighted regression-based residual signatures are highly informative of the T2-FLAIR mismatch sign and can identify isocitrate dehydrogenase-mutation and 1p/19q codeletion status with high predictive power. The utility of the proposed quantification of the T2-FLAIR mismatch sign can be potentially validated through a prospective multi-institutional study.

Subglottic and tracheal stenosis associated with coronavirus disease 2019.

BACKGROUND: Coronavirus disease 2019 critical care patients endure prolonged periods of intubation. Late tracheostomy insertion, large endotracheal tubes and high cuff pressures increase their risk of subglottic and tracheal stenosis. This patient cohort also often appears to have co-morbidities associated with laryngotracheal stenosis, including high body mass index and laryngopharyngeal reflux. METHODS: This paper presents three coronavirus disease 2019 patients who were intubated for a mean of 28 days before tracheostomy, leading to complex multi-level stenoses. RESULTS: All patients underwent multiple endoscopic tracheoplasty procedures and two required tracheal resections. There was a mean of 33.9 days between interventions. Coronavirus disease 2019 patients do not appear to respond as well to steroid, laser and balloon dilatation as other adult stenosis patients. CONCLUSION: Intubated coronavirus disease 2019 patients have an increased risk of laryngotracheal stenosis, as a result of multiple factors. Otolaryngology teams should be vigilant in investigating for this complication. International guidelines on time to tracheostomy should be followed, despite a diagnosis of coronavirus disease 2019.

A pan-Canadian prospective study of young women with breast cancer: the rationale and protocol design for the RUBY study.

Introduction: The understanding of the biology and epidemiology of, and the optimal therapeutic strategies for, breast cancer (bca) in younger women is limited. We present the rationale, design, and initial recruitment of Reducing the Burden of Breast Cancer in Young Women (ruby), a unique national prospective cohort study designed to examine the diagnosis, treatment, quality of life, and outcomes from the time of diagnosis for young women with bca. Methods: Over a 4-year period at 33 sites across Canada, the ruby study will use a local and virtual recruitment model to enrol 1200 women with bca who are 40 years of age or younger at the time of diagnosis, before initiation of any treatment. At a minimum, comprehensive patient, tumour, and treatment data will be collected to evaluate recurrence and survival. Patients may opt to complete patient-reported questionnaires, to provide blood and tumour samples, and to be contacted for future research, forming the core dataset from which 4 subprojects evaluating genetics, lifestyle factors, fertility, and local management or delivery of care will be performed. Summary: The ruby study will be the most comprehensive repository of data, biospecimens, and patient-reported outcomes ever collected with respect to young women with bca from the time of diagnosis, enabling research unique to that population now and into the future. This research model could be used for other oncology settings in Canada.

Willingness of women with early estrogen receptor-positive breast cancer to take adjuvant CDK4/6 inhibitors.

Background: The steady decline in breast cancer (bca) mortality has come at the cost of increasingly toxic and expensive adjuvant therapies. Trials evaluating the addition of 2 or 3 years of cyclin-dependent kinase 4/6 (cdk4/6) inhibitors to adjuvant endocrine therapy (et) are ongoing, but the willingness of patients to take such additional therapy is unknown. Methods: We surveyed 100 consecutive postmenopausal women with nonmetastatic estrogen receptor-positive bca who had initiated adjuvant et within the preceding 2 years. Participants were asked about perceived recurrence risk, bca worry, and overall health. They were then asked about their willingness to accept 2 years of treatment with an additional oral drug that would reduce recurrence by 40% for a range of baseline recurrence risks in 2 hypothetical scenarios. Results: Mean age of the 99 evaluable participants was 61.7 years. In the scenario with no drug toxicity, 85% of respondents were likely to accept the new drug for a reduction in recurrence to 30% from 50%, but only 49% would take the drug if risk was reduced to 3% from 5%. In a scenario with drug-induced fatigue, the corresponding drug acceptance rates were 55% and 39% respectively. For the second scenario, bca worry was correlated with increased willingness to take the drug, even for only a 2% absolute reduction in recurrence risk. Conclusions: The willingness of patients with estrogen receptor-positive bca to take an adjuvant cdk4/6 inhibitor will greatly depend on the expected benefit and toxicities described to them as well as on worry about bca recurrence.

North East London coronavirus disease 2019 protocol for diagnostics in two-week wait head and neck cancer patients.

BACKGROUND: The coronavirus disease 2019 pandemic requires urgent modification to existing head and neck cancer diagnosis and management practices. A protocol was established that utilises risk stratification, early investigation prior to clinical review and a reduction in aerosol generating procedures to lessen the risk of coronavirus disease 2019 spread. METHODS: Two-week wait referrals were stratified into low, intermediate and high risk. Low risk patients were referred back to primary care with advice; intermediate and high risk patients underwent investigation. Clinical encounters and aerosol generating procedures were minimised. A combined diagnostic and therapeutic surgical approach was undertaken where possible. RESULTS: Forty-one patients were used to assess feasibility. Thirty-one per cent were low risk, 35 per cent were intermediate and 33 per cent were high risk. Thirty-three per cent were discharged with no imaging. CONCLUSION: Implementing this protocol reduces the future burden on tertiary services, by empowering primary care physicians to re-refer low risk patients. The protocol is applicable across the UK and avoids diagnostic delay.

Ovarian function after chemotherapy in young breast cancer survivors.

BACKGROUND: As cure rates for breast cancer improve, there is increasing evidence that late effects of treatment-and impaired fertility in particular-are emerging as important concerns among young breast cancer survivors. Older reports have evaluated the occurrence of amenorrhea after treatment, but few data have been reported about the incidence of biochemical evidence for impaired ovarian function in patients who do not become overtly menopausal. METHODS: We conducted a cross-sectional study evaluating anti-Müllerian hormone (amh) in premenopausal chemotherapy-treated breast cancer survivors and control patients. Random serum levels of amh and other relevant clinical data were collected for 100 premenopausal chemotherapy-treated breast cancer survivors and 76 control subjects. Subgroup analyses were performed for women with regular menstrual cycles at the time of amh testing. RESULTS: After adjustment for age, amh was significantly lower in the overall group of patients receiving chemotherapy (p = 0.002) and in the subgroup reporting normal cycles (p = 0.03). Cyclophosphamide produced a significant dose-dependent reduction in amh (p < 0.001); trastuzumab was associated with increased amh in survivors with normal cycles. Overall, serum amh in survivors was roughly equivalent to that measured in control patients 12 years older. CONCLUSIONS: Young breast cancer survivors often experience significant impairment of ovarian function despite having normal menstrual cycles after treatment. Those results have important implications for patient counselling and the timing of possible referral to a fertility specialist.

User survey of Nanny Angel Network, a free childcare service for mothers with cancer.

PURPOSE: The purpose of the present study was to determine user satisfaction with Nanny Angel Network (nan), a free childcare service for mothers undergoing cancer treatment. METHODS: All 243 living mothers who had used the nan service were invited by telephone to participate in an online research survey; 197 mothers (81%) consented to participate. The survey, sent by e-mail, consisted of 39 items divided into these categories: demographics, supports, use, satisfaction, and general comments. RESULTS: Of the 197 mothers who consented to receive the e-mailed survey, 104 (53%) completed it. More than 90% of the mothers were very satisfied with the help and support from their Nanny Angel. Many mothers mentioned that the Nanny Angel was most helpful during treatment and medical appointments, with 75% also mentioning that their Nanny Angel helped them to adhere to their scheduled medical appointments. However, 64% felt that they had not received enough visits from their Nanny Angel. CONCLUSIONS: Satisfaction with the nan childcare provider was high, but mothers wished the service had been available to them more often. Our study highlights the importance of providing childcare to mothers with inadequate support systems, so as to allow for greater adherence to treatment and medical appointments, and for more time to recover.

Formal evaluation of PYNK: Breast Cancer Program for Young Women-the patient perspective.

PURPOSE: The aim of the present study was to assess patient satisfaction with pynk: Breast Cancer Program for Young Women so as to determine how the program might be improved and to provide feedback to donors. METHODS: All pynk patients who had consented to have their information entered in our database and who supplied us with their e-mail address were invited to complete a 58-item online questionnaire consisting of multiple choice and open-ended questions. Domains included demographics, provision of written and spoken information, support, infertility risk, research awareness, attitudes toward discharge, and general feedback. RESULTS: Of 120 pynk patients approached, 61 (51%) participated. More than 90% were satisfied or very satisfied with the timing, usefulness, and clarity of spoken and written information given, and 69% found the service and support provided by the nurse navigator to be the most helpful component of the program. Of those who had received systemic therapy, 93% recalled a health care provider initiating a discussion of the risk of treatment-related infertility, and 67% were referred to a fertility clinic. On the negative side, 11%-27% were unaware of various services provided by pynk, and 11% were unaware of pynk's ongoing research. One third of patients were unhappy or ambivalent about the prospect of discharge from the program. CONCLUSIONS: Patient satisfaction with this novel program for young women with breast cancer is high. This study highlights the critical role that the nurse navigator plays in patient support and dissemination of information. In contrast to other reported surveys of young cancer patients, pynk patients are routinely given the opportunity to undergo fertility preservation.

Labyrinthine sequestration secondary to auditory implantation: report of two cases and review of the literature.

BACKGROUND: Auditory implantation into the inner ear is increasingly performed for a variety of indications. Infective complications are rare, but when they occur they can have devastating consequences. CASE REPORTS: This paper reports two cases where vestibular sequestration of the bony labyrinth developed following implantation into the middle ear. CONCLUSION: To the authors' knowledge, these are the first reported cases where vestibular sequestration has resulted from auditory implant surgery. This paper outlines the radiological changes characteristic of this pathology. It also describes the surgical and conservative treatment options for this condition, challenging the previously accepted belief that affected patients always require aggressive surgical intervention.

Mucoepidermoid carcinoma in a thyroglossal duct remnant.

INTRODUCTION: Thyroglossal duct cysts (TDC) are common midline neck swellings resulting from embryological remnants of the thyroglossal duct. They often contain ectopic thyroid tissue and malignant transformation has been reported, most commonly to papillary thyroid carcinoma. Mucoepidermoid carcinoma (MEC) usually occurs in the salivary glands and only rarely in the thyroid. This is the first case of a MEC occurring within a thyroglossal duct remnant. PRESENTATION OF A CASE: A 73 year old lady presented with a thyroglossal duct cyst. She declined surgical excision, as she was adamant she wanted to avoid surgery. The neck mass rapidly enlarged at two years following initial diagnosis. Fine needle aspiration cytology was suspicious for carcinoma. She underwent total thyroidectomy and selective central compartment neck dissection with adjuvant radiotherapy. She remains alive and well two years post treatment. DISCUSSION: Mucoepidermoid carcinoma is the most common malignant neoplasm of salivary glands, although it has rarely been reported in diverse locations including the thyroid, lung and pancreas. To the best of our knowledge, this is the first reported case of mucoepidermoid carcinoma arising from a thyroglossal duct remnant. CONCLUSION: This case adds weight to the literature favouring surgical excision of thyroglossal duct remnants due to the risk of malignant transformation.

Efficacy of an educational intervention on family physicians' risk assessment and management of colorectal cancer.

We developed a point-of-care tool indicating risk categories for colorectal cancer (CRC) based on family history (FH) and management recommendations tailored to risk. The study objective was to determine if this CRC Risk Triage/Management Too would enable family physicians (FPs) to appropriately triage and make screening and genetics referral recommendations for patients with CRC FH. Baseline questionnaires were mailed to a random sample of FPs in Ontario and Newfoundland, Canada. Participants were asked to use the tool for 3 months and then complete a follow-up questionnaire. The primary outcomes were correct responses to questions regarding CRC risk category, screening method, starting age, frequency, and decision to refer to genetics, for eight clinical vignettes. The study was completed by 75/121 (62 %) participating FPs. Most (77 %) agreed they routinely recommended fecal occult blood testing for average risk patients age ≥50. This did not change significantly following the intervention. There was a significant increase in confidence in CRC risk assessment (52 % pre; 88 % post; p < 0.001), correct management recommendations for patients with CRC FH (51 % pre; 84 % post; p < 0.001), and improvement in total mean scores on outcome measures for all vignettes. Most (90 %) agreed the tool would improve practice. Receipt of the CRC Risk Triage/Management Tool was associated with improvement in FPs' CRC risk assessment, screening, and genetics referral recommendations for clinical vignettes. This demonstrates the value of point-of-care tools and illustrates a process for development, evaluation, and dissemination of tools needed by FPs if potential impacts of genomic advances are to be achieved.