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.

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.

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.

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.

Development and pilot testing of an online intervention to support young couples' coping and adjustment to breast cancer.

Couplelinks is an original, professionally facilitated online intervention tailored to the unique challenges facing young women with breast cancer and their male partners. The purpose of this evaluation was to determine the feasibility and acceptability of the intervention and areas for improvement. Sixteen couples were sequentially enrolled over an 18-month period. Couples provided feedback via a treatment satisfaction survey, and post-treatment interviews with a sub-group of participants. Qualitative information was analysed for themes relevant to the program's acceptability, perceived benefits and limitations, and directions for improvement. Of the 16 couples who enrolled, six completed four modules or less, and 10 completed the entire program. Completers reported satisfaction with the program overall, as well as with the website useability and professional facilitation. Reported benefits were: enhanced communication and self-other knowledge; creation of opportunities for meaningful, cancer-related discussion; affirmation of relationship strengths; and a greater sense of closeness between partners. The main reported limitation was how program participation disrupted the couple's usual routine. Themes related to non-completion suggest that partners with particularly elevated relational or illness-related distress, or with differential levels of motivation, are less likely to finish. These findings have led to targeted improvements to the website and intervention protocol.

Variants of unknown significance in BRCA testing: impact on risk perception, worry, prevention and counseling.

BACKGROUND: Sequence-based BRCA testing can identify variants of unknown significance (VUS). Relatively little is known about how well a test outcome of VUS is understood by patients and referring physicians, and whether genetic counselors have an interest in the development of VUS management guidelines. DESIGN: Self-administered questionnaires were completed by 36 VUS counselees, 75 women with a BRCA mutation and 33 with no mutation found (NMF). We also surveyed 24 genetic counselors and 22 referring family physicians. RESULTS: One-third of VUS failed to recall the clinical significance of their result. Incorrect recall was significantly higher among VUS with high-school-only education (70% versus 19%, P = 0.02). Risk perception, cancer worry and uptake of surveillance and risk-reducing surgeries among VUS counselees were more similar to NMF than to mutation carriers. Genetic counselors accurately predicted the difficulties counselees would have with a VUS result and identified the need for VUS management guidelines. Referring physicians unanimously stated that genetic testing was indicated for unaffected siblings of VUS carriers. CONCLUSIONS: While VUS seems to be correctly perceived by counselees as more similar to NMF than to a pathogenic mutation, miscomprehension of VUS is more common, particularly in counselees with lower education. VUS-related educational interventions for both VUS counselees and their referring physicians are needed. We encourage the development of national VUS-related guidelines for genetic counselors.

Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families.

The hereditary breast cancer gene BRCA2 was recently cloned and is believed to account for almost half of site-specific breast cancer families and the majority of male breast cancer families. We screened 49 site-specific breast cancer families for mutations in the BRCA2 gene using single strand conformation analysis (SSCA) followed by direct sequencing. We found mutations in eight families, including all four families with male breast cancer. The eight mutations were small deletions with the exception of a single nonsense mutation, an all were predicted to interrupt the BRCA2 coding sequence and to lead to a truncated protein product. Other factors which predicted the presence of a BRCA2 mutation included a case of breast cancer diagnosed at age 35 or below (P = 0.01) and a family history of pancreatic cancer (P = 0.03). Two mutations were seen twice, including a 8535delAG, which was detected in two French Canadian families. Our results suggest the possibility that the proportion of site-specific breast cancer families attributable to BRCA2 may be overestimated.

pynk : Breast Cancer Program for Young Women.

CONSIDER THIS SCENARIO: A 35-year-old recently married woman is referred to a surgeon because of a growing breast lump. After a core biopsy shows cancer, she undergoes mastectomy for a 6-cm invasive lobular cancer that has spread to 8 axillary nodes. By the time she sees the medical oncologist, she is told that it is too late for a fertility consultation, and she receives a course of chemotherapy. At clinic appointments, she seems depressed and admits that her husband has been less supportive than she had hoped. After tamoxifen is started, treatment-related sexuality problems and the probability of infertility contribute to increasing strain on the couple's relationship. Their marriage ends two years after the woman's diagnosis.Six years after her diagnosis, this woman has completed all treatment, is disease-free, and is feeling extremely well physically. However, she is upset about being postmenopausal, and she is having difficulty adopting a child as a single woman with a history of breast cancer. Could this woman and her husband have been offered additional personalized interventions that might have helped them better cope with the breast cancer diagnosis and the effects of treatment?Compared with their older counterparts, young women with breast cancer often have greater and more complex supportive care needs. The present article describes the goals, achievements, and future plans of a specialized interdisciplinary program-the first of its kind in Canada-for women 40 years of age and younger newly diagnosed with breast cancer. The program was created to optimize the complex clinical care and support needs of this population, to promote research specifically targeting issues unique to young women, and to educate the public and health care professionals about early detection of breast cancer in young women and about the special needs of those women after their diagnosis.

Long-term results of screening with magnetic resonance imaging in women with BRCA mutations.

BACKGROUND: The addition of breast magnetic resonance imaging (MRI) to screening mammography for women with BRCA mutations significantly increases sensitivity, but there is little data on clinical outcomes. We report screening performance, cancer stage, distant recurrence rate, and breast cancer-specific mortality in our screening study. METHODS: From 1997 to 2009, 496 women aged 25 to 65 years with a known BRCA1/2 mutation, of whom 380 had no previous cancer history, were enrolled in a prospective screening trial that included annual MRI and mammography. RESULTS: In 1847 screening rounds, 57 cancers were identified (53 screen-detected, 1 interval, and 3 incidental at prophylactic mastectomy), of which 37 (65%) were invasive. Sensitivity of MRI vs mammography was 86% vs 19% over the entire study period (P<0.0001), but was 74% vs 35% from 1997 to 2002 (P=0.02) and 94% vs 9% from 2003 to 2009 (P<0.0001), respectively. The relative sensitivities of MRI and mammography did not differ by mutation, age, or invasive vs non-invasive disease. Of the incident cancers, 97% were Stage 0 or 1. Of 28 previously unaffected women diagnosed with invasive cancer, 1 BRCA1 mutation carrier died following relapse of a 3 cm, node-positive breast cancer diagnosed on her first screen at age 48 (annual breast cancer mortality rate=0.5%). Three patients died of other causes. None of the 24 survivors has had a distant recurrence at a median follow-up of 8.4 years since diagnosis. CONCLUSION: Magnetic resonance imaging surveillance of women with BRCA1/2 mutations will detect the majority of breast cancers at a very early stage. The absence of distant recurrences of incident cancers to date is encouraging. However, longer follow-up is needed to confirm the safety of breast surveillance.

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.

Impact of MRI surveillance and breast cancer detection in young women with BRCA mutations.

Based on several observational studies that have yielded consistent results, the combination of annual magnetic resonance imaging (MRI) plus mammography is now the standard of care for screening women with BRCA mutations who decline risk-reducing mastectomy. However, many of these women will develop breast cancer at a young age and, while most of these cancers will be very early stage, oncologists need to be aware of the unique issues faced by women in this age group due to the diagnosis and treatment. Fear of death, loss of fertility, premature menopause, relationship stress, career disruption and financial losses are only some of the problems that are either unique to young women or much more pronounced in this age group. Urgent referral to a fertility specialist of any woman who has not yet completed her family should be made as soon as the possible need for systemic treatment is recognized. The oncologist should also have a low threshold for referring young women to professionals experienced in navigating young women and their families through the psychosocial trauma of a breast cancer diagnosis.

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.

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.

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.

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.