Comparison of Clinical Breast Exam to Breast MRI Surveillance in Patients Following Nipple-Sparing Mastectomy.

BACKGROUND: Nipple sparing mastectomy (NSM) is increasingly being performed for patients with breast cancer. However, optimal postoperative surveillance has not been defined. METHODS: A prospectively maintained database identified patients with in-situ and invasive cancer who underwent NSM between 2007-2021. Clinical data on postoperative breast surveillance and interventions were collected. Patients who had MRI surveillance versus clinical breast exam (CBE) alone were compared with respect to tumor characteristics, recurrence, and survival. RESULTS: A total of 483 NSMs were performed on 399 patients. 255 (63.9%) patients had invasive ductal carcinoma, 31 (7.8%) invasive lobular carcinoma, 92 (23.1%) DCIS, 6 (1.5%) mixed ductal and lobular carcinoma, 9 (2.3%) others, and 6 (1.5%) unknown. Postoperatively, 265 (66.4%) patients were followed with CBE alone and 134 (33.6%) had surveillance MRIs. At a median follow-up of 33 months, 20 patients (5.0%) developed in-breast recurrence, 6 patients had (1.5%) an axillary recurrence, and 28 with (7.0%) distant recurrence. 14 (53.8%) LRR were detected in the CBE group and 12 (46.2%) were detected in the MRI group (P = .16). Overall survival (OS) was 99%, with no difference in OS between patients who had CBE alone versus MRI (P = .46). MRI was associated with higher biopsy rates compared to CBE alone (15.8% vs. 7.8%, P = .01). CONCLUSIONS: Compared to CBE alone, the use of screening MRI following NSM results in higher rate of biopsy and no difference in overall survival.

Understanding Treatment Decision-Making in Older Women With Breast Cancer: A Survey-Based Study.

INTRODUCTION: For women ≥70 y old with early-stage hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, the national guidelines recommend the omission of sentinel lymph node biopsy (SLNB) and post-lumpectomy radiotherapy. However, national-level data suggest these treatments remain common. We utilized a survey-based approach to explore patient-level factors driving overutilization. METHODS: We recruited women ≥70 y old with early-stage hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer within 6 mo of surgery. An exploratory cross-sectional survey captured information on offered and pursued treatments, the importance of patient-centered outcomes, and the influence of each outcome on treatment decision-making. Descriptive statistics were used for analysis. RESULTS: 31/51 patients completed the survey with a response rate of 61%. Most patients (86%) received a lumpectomy. Twenty-eight percent of patients received SLNB, and 56% of lumpectomy patients underwent adjuvant radiotherapy. When considering treatment options, the patient-centered outcomes, most important for decision-making, were overall survival, breast-specific survival, and preventing local recurrence, while breast appearance, financial costs, and avoiding the need for pills (endocrine therapy) were the least important. CONCLUSIONS: Patients' treatment decisions align with their values. The correlation between patient-stated values and treatment decisions suggests a perceived mortality benefit of low-value SLNB and radiotherapy. These findings can inform targeted efforts to deimplement low-value care in breast cancer through patient-focused tools and education.

Incorporating Value-Based Decisions in Breast Cancer Treatment Algorithms.

Given the excellent prognosis and availability of evidence-based treatment, patients with early-stage breast cancer are at risk of overtreatment. In this review, we summarize key opportunities to incorporate value-based decisions to optimize the delivery of high-value treatment across the breast cancer care continuum.

De-Implementation of Low-Value Care for Women 70 Years of Age or Older with Low-Risk Breast Cancer During the COVID-19 Pandemic.

BACKGROUND: Older women with early-stage estrogen receptor-positive (ER+) invasive breast cancer (IBC) are at risk for overtreatment. Guidelines allow for sentinel lymph node biopsy (SLNB) and radiotherapy omission after breast-conserving surgery (BCS) for women 70 years of age or older with T1, clinical node negativity (cN0), and ER+ IBC. The study objective was to evaluate radiotherapy and SLNB de-implementation in older women with low-risk IBC after the resource limitations of the COVID-19 pandemic. METHODS: An institutional database was analyzed to identify women 70 years of age or older who received BCS for IBC from 2012 to 2022. The patients were divided into two cohorts: (1) patients with low-risk IBC (pT1, cN0, and ER+/HER2-) who were eligible for radiotherapy and SLNB omission and (2) patients with high-risk IBC (pT2-T4, cN+, ER-, or HER2+) who were ineligible for therapy omission. Clinicopathologic variables in both cohorts were analyzed. RESULTS: The study enrolled 881 patients. For the patients with low-risk IBC, the annual rates of radiotherapy were stable from 2012 to 2019. However, radiotherapy utilization decreased significantly from 2020 to 2022 (58% in 2012 vs 36% in 2022; p = 0.04). In contrast, radiotherapy usage among the patients with high-risk IBC was stable from 2012 to 2022 (79% in 2012 vs 79% in 2022; p = 0.95). Among the patients with low-risk IBC, SLNB rates decreased from 86% in 2012 to 56% in 2022, but this trend predated those in 2020. The factors significantly associated with SLNB and receipt of radiotherapy among the patients with low-risk IBC were younger age, larger tumors, grade 3 disease, and involved nodal status (p < 0.01). CONCLUSION: This study demonstrated appropriate and sustained de-escalation of radiotherapy in older women with low-risk IBC after the COVID-19 pandemic.

Avoiding Overtreatment of Women ≥70 With Early-Stage Breast Cancer: A Provider-Level Deimplementation Strategy.

INTRODUCTION: National guidelines recommend against routine axillary staging with sentinel lymph node biopsy (SLNB) and adjuvant radiotherapy (RT) in women ≥70 y with early-stage, hormone receptor-positive, HER2-negative breast cancer and clinically negative axilla; however, these practices remain common. METHODS: We conducted a prospective pilot study from August 2021 to 2022 using an intervention targeting breast surgeons and radiation oncologists in Michigan that aimed to reduce SLNB and RT in eligible patients. The intervention consisted of (1) a geriatric assessment, (2) an assessment of the patient's medical maximizing-minimizing preferences, and (3) a tailored script with counterpoints to reasons patients commonly seek SLNB or RT. At the end of the study period, participants completed a survey providing feedback with the primary outcomes being: acceptability, appropriateness, feasibility, and intention and motivation to use the materials based on validated measures. RESULTS: Participants (n = 23) included 15 breast surgeons and 8 radiation oncologists. Collectively, the materials were used with 115 patients. Considering all materials holistically, acceptability, appropriateness, and feasibility of the intervention were high; participants also intended and were motivated to use the intervention. Scores across all measures were highest for the geriatric assessment and lowest for the tailored script. The major barriers to using the intervention were limited time and instances of disagreement on treatment recommendations among surgeons and radiation oncologists. CONCLUSIONS: The omission of SLNB and adjuvant RT should be discussed in appropriately selected patients. A multifaceted provider-level deimplementation strategy may be an effective means for achieving this goal.

Facility-Level Variation of Low-Value Breast Cancer Treatments in Older Women with Early-Stage Breast Cancer: Analysis of a Statewide Claims Registry.

BACKGROUND: Since 2004, national guidelines have supported the omission of sentinel lymph node biopsy (SLNB) and radiotherapy for women ≥ 70 years of age with early-stage, hormone receptor-positive (HR+) breast cancer, but many women continue to receive at least one of these services. Provider- and patient-level factors may contribute to persistent utilization, but the role of facility-level factors is unknown. We aimed to determine facility-level variation of SLNB and adjuvant radiotherapy utilization in older women with early-stage, HR+ breast cancer undergoing breast-conserving surgery (BCS). Additionally, we aimed to explore factors associated with SLNB and radiotherapy utilization and the intra-facility correlation in their utilization. METHODS: We conducted a retrospective cohort study using a statewide registry of claims data. We included women ≥70 years of age diagnosed with breast cancer who underwent BCS from 2012 to 2019 at 80 hospitals in the Michigan Value Collaborative. The main outcome was inter-facility rates and variation of SLNB and radiotherapy, as well as intra-facility correlation in their utilization. RESULTS: The cohort included 7253 women (median age 77 years). Only 20% (n = 1440) underwent BCS alone, whereas 71% (n = 5122) underwent SLNB and 52% (n = 3793) received radiotherapy. Inter-facility rates of SLNB ranged from 35 to 82% (median 70%), and radiotherapy ranged from 19 to 72% (median 49%). SLNB and radiotherapy were positively correlated (r = 0.27, p = 0.016). CONCLUSIONS: SLNB and radiotherapy rates remain high with significant variation in utilization at the facility level. High utilizers of SLNB are likely to be high utilizers of radiotherapy, suggesting the opportunity for strategic targeting of these facilities and their clinicians.

Statewide Episode Spending Variation of Mastectomy for Breast Cancer.

BACKGROUND: Centralizing complex cancer operations, such as pancreatectomy and esophagectomy, has been shown to increase value, largely due to reduction in complications. For high-volume operations with low complication rates, it is unknown to what degree value varies between facilities, or by what mechanism value may be improved. To identify possible opportunities for value enhancement for such operations, we sought to describe variations in episode spending for mastectomy with a secondary aim of identifying patient- and facility-level determinants of variation. STUDY DESIGN: Using the Michigan Value Collaborative risk-adjusted, price-standardized claims data, we evaluated mean spending for patients undergoing mastectomy at 74 facilities (n = 7,342 patients) across the state of Michigan. Primary outcomes were 30- and 90-day episode spending. Using linear mixed models, facility- and patient-level factors were explored for association with spending variability. RESULTS: Among 7,342 women treated across 74 facilities, mean 30-day spending by facility ranged from $11,129 to $20,830 (median $14,935). Ninety-day spending ranged from $17,303 to $31,060 (median $23,744). Patient-level factors associated with greater spending included simultaneous breast reconstruction, bilateral surgery, length of stay, and readmission. Among women not undergoing reconstruction, variation persisted, and length of stay, bilateral surgery, and readmission were all associated with increased spending. CONCLUSION: Michigan hospitals have significant variation in spending for mastectomy. Reducing length of stay through wider adoption of same-day discharge for mastectomy and reducing the frequency of bilateral surgery may represent opportunities to increase value, without compromising patient safety or oncologic outcomes.

Using Tailored Messages to Target Overuse of Low-Value Breast Cancer Care in Older Women.

BACKGROUND: National recommendations allow for the omission of sentinel lymph node biopsy (SLNB) and post-lumpectomy radiotherapy in women ≥ 70 y/o with early-stage, hormone-receptor positive invasive breast cancer, but these therapies remain common. Previous work demonstrates an individual's maximizing-minimizing trait-an inherent preference for more or less medical care-may influence the preference for low-value care. MATERIALS AND METHODS: We recruited an equal number of women ≥ 70 yrs who were maximizers, minimizers, or neutral based on a validated measure between September 2020 and November 2020. Participants were presented a hypothetical breast cancer diagnosis before randomization to one of three follow-up messages: maximizer-tailored, minimizer-tailored, or neutral. Tailored messaging aimed to redirect maximizers and minimizers toward declining SLNB and radiotherapy. The main outcome measure was predicted probability of choosing SLNB or radiotherapy. RESULTS: The final analytical sample (n = 1600) was 515 maximizers (32%), 535 neutral (33%) and 550 (34%) minimizers. Higher maximizing tendency positively correlated with electing both SLNB and radiotherapy on logistic regression (P < 0.01). Any tailoring (maximizer- or minimizer-tailored) reduced preference for SLNB in maximizing and neutral women but had no effect in minimizing women. Tailoring had no impact on radiotherapy decision, except for an increased probability of minimizers electing radiotherapy when presented with maximizer-tailored messaging. CONCLUSIONS: Maximizing-minimizing tendencies are associated with treatment preferences among women facing a hypothetical breast cancer diagnosis. Targeted messaging may facilitate avoidance of low-value breast cancer care, particularly for SLNB.

Incremental Spending Associated with Low-Value Treatments in Older Women with Breast Cancer.

BACKGROUND: In most women ≥ 70 years old with hormone-receptor-positive breast cancer, axillary staging and adjuvant radiotherapy provide no survival advantage over surgery and hormone therapy alone. Despite recommendations for their omission, sentinel lymph node biopsy (SLNB) and adjuvant radiotherapy rates remain high. While treatment side effects are well documented, less is known about the incremental spending associated with SLNB and adjuvant radiotherapy. METHODS: Using a statewide multipayer claims registry, we examined spending associated with breast cancer treatment in a retrospective cohort of women ≥ 70 years old undergoing surgery. RESULTS: 9074 women ≥70 years old underwent breast cancer resection between 2012 and 2019, with 78% (n = 7122) receiving SLNB and/or adjuvant radiotherapy within 90 days of surgery. Women undergoing SLNB were more likely to receive radiation (51% vs. 28%; p < 0.001 and OR = 2.68). Average 90-day spending varied substantially based upon treatment received, ranging from US$10,367 (breast-conserving surgery alone) to US$27,370 (mastectomy with SLNB and adjuvant radiotherapy). The relative increases in 90-day treatment spending in the breast-conserving surgery cohort was 65% for SLNB, 82% for adjuvant radiotherapy, and 120% for both treatments. CONCLUSIONS: SLNB and adjuvant radiotherapy have significant spending implications in older women with breast cancer, even though they are unlikely to improve survival.

A Health Systems Ethical Framework for De-implementation in Health Care.

INTRODUCTION: Unnecessary health care not only drive up costs, but also contribute to avoidable patient harms, underscoring an ethical obligation to eliminate practices which are harmful, lack evidence, and prevent spending on more beneficial services. To date, de-implementation ethics discussions have been limited and focused on clinical ethics principles. An analysis of de-implementation ethics in the broader context of the health care system is lacking. METHODS: To better understand the ethical considerations of de-implementation, recognizing it as a health care systems issue, we applied Krubiner and Hyder's bioethical framework for health systems activity. We examine ethics principles relevant to de-implementation, which either call for or facilitate the reduction of low value surgery. RESULTS AND DISCUSSION: From 11 health systems principles proposed by Krubiner and Hyder, we identified the 5 principles most pertinent to the topic of de-implementation: evidence and effectiveness, transparency and public engagement, efficiency, responsiveness, and collaboration. An analysis of de-implementation through the lens of these principles not only supports de-implementation but proves an obligation at the health system level to eliminate low value care. Recognizing the challenge of defining "value," the proposed framework may increase the legitimacy and objectivity of de-implementation. CONCLUSIONS: While there is no single ideal ethical framework from which to approach de-implementation, a health systems framework allows for consideration of the systems-level factors impacting de-implementation. Framing de-implementation as a health systems issue with systems-wide ethical implications empowers providers to think about new ways to approach potential roadblocks to reducing low-value care.

LIMIT is an immunogenic lncRNA in cancer immunity and immunotherapy.

Major histocompatibility complex-I (MHC-I) presents tumour antigens to CD8+ T cells and triggers anti-tumour immunity. Humans may have 30,000-60,000 long noncoding RNAs (lncRNAs). However, it remains poorly understood whether lncRNAs affect tumour immunity. Here, we identify a lncRNA, lncRNA inducing MHC-I and immunogenicity of tumour (LIMIT), in humans and mice. We found that IFNγ stimulated LIMIT, LIMIT cis-activated the guanylate-binding protein (GBP) gene cluster and GBPs disrupted the association between HSP90 and heat shock factor-1 (HSF1), thereby resulting in HSF1 activation and transcription of MHC-I machinery, but not PD-L1. RNA-guided CRISPR activation of LIMIT boosted GBPs and MHC-I, and potentiated tumour immunogenicity and checkpoint therapy. Silencing LIMIT, GBPs and/or HSF1 diminished MHC-I, impaired antitumour immunity and blunted immunotherapy efficacy. Clinically, LIMIT, GBP- and HSF1-signalling transcripts and proteins correlated with MHC-I, tumour-infiltrating T cells and checkpoint blockade response in patients with cancer. Together, we demonstrate that LIMIT is a cancer immunogenic lncRNA and the LIMIT-GBP-HSF1 axis may be targetable for cancer immunotherapy.

A novel C-terminal Hsp90 inhibitor KU758 synergizes efficacy in combination with BRAF or MEK inhibitors and targets drug-resistant pathways in BRAF-mutant melanomas.

Melanoma remains the most aggressive and fatal form of skin cancer, despite several FDA-approved targeted chemotherapies and immunotherapies for use in advanced disease. Of the 100 350 new patients diagnosed with melanoma in 2020 in the US, more than half will develop metastatic disease leading to a 5-year survival rate <30%, with a majority of these developing drug-resistance within the first year of treatment. These statistics underscore the critical need in the field to develop more durable therapeutics as well as those that can overcome chemotherapy-induced drug resistance from currently approved agents. Fortunately, several of the drug-resistance pathways in melanoma, including the proteins in those pathways, rely in part on Hsp90 chaperone function. This presents a unique and novel opportunity to simultaneously target multiple proteins and drug-resistant pathways in this disease via molecular chaperone inhibition. Taken together, we hypothesize that our novel C-terminal Hsp90 inhibitor, KU758, in combination with the current standard of care targeted therapies (e.g. vemurafenib and cobimetinib) can both synergize melanoma treatment efficacy in BRAF-mutant tumors, as well as target and overcome several major resistance pathways in this disease. Using in vitro proliferation and protein-based Western Blot analyses, our novel inhibitor, KU758, potently inhibited melanoma cell proliferation (without induction of the heat shock response) in vitro and synergized with both BRAF and MEK inhibitors in inhibition of cell migration and protein expression from resistance pathways. Overall, our work provides early support for further translation of C-terminal Hsp90 inhibitor and mitogen-activated protein kinase pathway inhibitor combinations as a novel therapeutic strategy for BRAF-mutant melanomas.

Identification of promotion and prevention associated surgeon behaviors in the operating room to facilitate resident self-regulated learning.

BACKGROUND: The regulatory focus theory (RFT) posits that people can pursue goals with a promotion or prevention focus. Greater alignment of RFT motivational styles between faculty and residents may enhance resident operative autonomy. This study establishes a set of faculty behaviors residents can identify to infer faculty motivational styles. METHODS: 10 behaviors associated with promotion and prevention motivational styles were identified. General surgery residents rated faculty on how strongly they exhibit these behaviors. Faculty conducted a self-assessment of how strongly they exhibit these behaviors. RESULTS: There is a positive correlation between resident and faculty ratings for the promotion-associated behaviors of "works quickly," "high energy," and "mostly provides broad oversight," and for the prevention-associated behaviors of "works slowly and deliberately," "quiet and calm," and "preference for vigilant strategies." CONCLUSION: Residents can observe faculty operative behaviors to infer faculty motivational styles. Residents may use this knowledge to adjust to faculty motivational styles and enhance operative interactions.

Variations in Persistent Use of Low-Value Breast Cancer Surgery.

Importance: Through the Choosing Wisely campaign, surgical specialties identified 4 low-value breast cancer operations. Preliminary data suggest varying rates of deimplementation and have identified patient-level and clinician-level determinants of continued overuse. However, little information exists about facility-level variation or determinants of differential deimplementation. Objective: To identify variation and determinants of persistent use of low-value breast cancer surgical care. Design, Setting, and Participants: Retrospective cohort study in which reliability-adjusted facility rates of each procedure were calculated using random-intercept hierarchical logistic regression before and after evidence demonstrated that each procedure was unnecessary. The National Cancer Database is a prospective cancer registry of patients encompassing approximately 70% of all new cancer diagnoses from more than 1500 facilities in the United States. Data were analyzed from November 2019 to August 2020. The registry included women 18 years and older diagnosed as having breast cancer between 2004 and 2016 and meeting inclusion criteria for each Choosing Wisely recommendation. Main Outcomes and Measures: Rate of each low-value breast cancer procedure based on facility type and breast cancer volume categories before and after the release of data supporting each procedure's omission. Results: The total cohort included 920 256 women with a median age of 63 years. Overall, 86% self-identified as White, 10% as Black, 3% as Asian, and 4.5% as Hispanic. Most women in this cohort were insured (51% private and 47% public), were living in a metropolitan or urban area (88% and 11%, respectively), and originated from the top half of income-earning households (65.5%). While there was significant deimplementation of axillary lymph node dissection and lumpectomy reoperation in response to guidelines supporting omission of these procedures, rates of contralateral prophylactic mastectomy and sentinel lymph node biopsy in older women increased during the study period. Academic research programs and high-volume facilities overall demonstrated the greatest reduction in use of these low-value procedures. There was significant interfacility variation for each low-value procedure. Facility-level axillary lymph node dissection rates ranged from 7% to 47%, lumpectomy reoperation rates ranged from 3% to 62%, contralateral prophylactic mastectomy rates ranged from 9% to 67%, and sentinel lymph node biopsy rates ranged from 25% to 97%. Pearson correlation coefficient for each combination of 2 of the 4 procedures was less than 0.11, suggesting that hospitals were not consistent in their deimplementation performance across all 4 procedures. Many were high outliers in one procedure but low outliers in another. Conclusions and Relevance: Interfacility variation demonstrates a performance gap and an opportunity for formal deimplementation efforts targeting each procedure. Several facility-level characteristics were associated with differential deimplementation and performance.

Trends in Contralateral Prophylactic Mastectomy Utilization for Small Unilateral Breast Cancer.

BACKGROUND: For average-risk women with unilateral breast cancer, contralateral prophylactic mastectomy (CPM) offers no survival benefit and contributes to increased costs and patient harm. Despite recommendations from professional societies against CPM, utilization of this service is increasing, partly due to patients' desire for breast symmetry when undergoing mastectomy. Most women with small tumors are candidates for breast-conserving surgery (BCS) and could avoid CPM. We describe CPM utilization in women with small, unilateral tumors, and identify determinants of possible overuse. METHODS: Using the National Cancer Database, we identified women with unilateral, T1 breast cancer. We evaluated utilization of BCS, unilateral mastectomy, and CPM and assessed patient, tumor, and facility factors associated with CPM. RESULTS: Of 765,487 women with small, unilateral breast cancer, 69% underwent BCS and 31% chose mastectomy. Of 176,673 women ≥70 y, 75% underwent BCS and 25% chose mastectomy. CPM rates in both cohorts have increased since 2006. Decreased adjuvant radiotherapy in older women was associated with increased BCS rates. Patient factors (younger age, white race, private insurance, and breast reconstruction), tumor factors (lobular histology, higher grade, and human epidermal growth factor receptor 2 positive/estrogen receptor negative status), and facility factors (type and geographic location) were associated with increased CPM rates compared with unilateral mastectomy in multivariable models. CONCLUSIONS: Most women with small unilateral breast cancer are candidates for BCS, yet one-third elects to undergo a mastectomy, of which a rising percentage opts for CPM. Tailoring deimplementation strategies to factors influencing treatment may help reduce CPM utilization and associated financial toxicity, pain, and disability.

Trends in Breast Cancer Treatment De-Implementation in Older Patients with Hormone Receptor-Positive Breast Cancer: A Mixed Methods Study.

INTRODUCTION: Guidelines allow for the omission of sentinel lymph node biopsy (SLNB) and post-lumpectomy radiotherapy in women ≥ 70 years of age with hormone receptor-positive (HR +) breast cancer. Despite this, national data suggest these procedures have not been widely de-implemented. OBJECTIVES: Our objectives were to evaluate trends in SLNB and post-lumpectomy radiotherapy utilization in patients who are eligible for omission, and evaluate patient preferences as a target for de-implementation of low-value care. METHODS: We performed a sequential explanatory mixed-methods study by first analyzing an institutional database of patients ≥ 70 years of age with HR + breast cancer who received surgical treatment from 2014 to 2018. Based on the quantitative data, we conducted semi-structured interviews with women identified as high or low utilizers of breast cancer treatments to elicit patient perspectives on de-implementation. RESULTS: SLNB and post-lumpectomy radiotherapy were performed in 68% and 43% of patients, respectively, who met the criteria for omission. There was a significant decrease in SLNB rates from 2014 to 2018. Forty-nine percent of patients were classified as high utilizers and 26% were classified as low utilizers. Qualitative analysis found that the most important factors influencing decision making regarding SLNB and post-lumpectomy radiotherapy omission for both high and low utilizers were trust in their provider and a desire for peace of mind. CONCLUSIONS: Despite efforts to de-implement low-value care, older women with HR + breast cancer remain at risk of overtreatment. Patient perspectives suggest that multi-level de-implementation strategies will need to target provider practice patterns and patient-provider communication to promote high-quality decision making and reduction in breast cancer overtreatment.

A novel heat shock protein inhibitor KU757 with efficacy in lenvatinib-resistant follicular thyroid cancer cells overcomes up-regulated glycolysis in drug-resistant cells in vitro.

BACKGROUND: Patients with advanced differentiated thyroid cancer develop resistance to lenvatinib treatment from metabolic dysregulation. Heat shock protein 90 is a molecular chaperone that plays an important role in glycolysis and metabolic pathway regulation. We hypothesize that lenvatinib-resistant differentiated thyroid cancer cells will have an increased dependency on glycolysis and that a novel C-terminal heat shock protein 90 inhibitor (KU757) can effectively treat lenvatinib-resistant cells by targeting glycolysis. METHODS: Inhibitory concentration 50 values of thyroid cancer cells were determined by CellTiter-Glo assay (Promega Corp, Madison, WI). Glycolysis was measured through Seahorse experiments. Reverse transcription-polymerase chain reaction and Western blot evaluated glycolytic pathway genes/proteins. Exosomes were isolated/validated by nanoparticle tracking analysis and Western blot. Differentially expressed long non-coding ribonucleic acids in exosomes and cells were evaluated using quantitative polymerase chain reaction. RESULTS: Extracellular acidification rate demonstrated >2-fold upregulation of glycolysis in lenvatinib-resistant cells versus parent cells and was downregulated after KU757 treatment. Lenvatinib-resistant cells showed increased expression of the glycolytic genes lactic acid dehydrogenase, pyruvate kinase M1/2, and hexokinase 2. KU757 treatment resulted in downregulation of these genes and proteins. Several long non-coding ribonucleic acids associated with glycolysis were significantly upregulated in WRO-lenvatinib-resistant cells and exosomes and downregulated after KU757 treatment. CONCLUSION: Lenvatinib resistance leads to increased glycolysis, and KU757 effectively treats lenvatinib-resistant cells and overcomes this increased glycolysis by targeting key glycolytic genes, proteins, and long non-coding ribonucleic acids.

Medical Maximizing-Minimizing Preferences in Relation to Low-Value Services for Older Women with Hormone Receptor-Positive Breast Cancer: A Qualitative Study.

BACKGROUND: Multiple studies have demonstrated the safety of omitting therapies in older women with breast cancer. Despite de-implementation guidelines, up to 65% of older women continue to receive one or more of these low-value services. Previous work has investigated the role of both provider and patient attitudes as barriers to de-implementation; however, the importance of the patient's maximizing-minimizing preferences within this context remains unclear. METHODS: In this qualitative study, we conducted 30 semi-structured interviews with women ≥ 70 years of age without a previous diagnosis of breast cancer to elicit perspectives on breast cancer treatment in relation to their medical maximizing-minimizing preferences, as determined by the single-item maximizer-minimizer elicitation question (MM1). We used an interpretive description approach in analysis to produce a thematic survey. RESULTS: Participants were relatively evenly distributed across the MM1 (minimizer, n = 8; neutral, n = 13; maximizer, n = 9). Despite being told of recommendations allowing for the safe omission of sentinel lymph node biopsy and post-lumpectomy radiotherapy, maximizers consistently stated preferences for more medical intervention and aggressive therapies over minimizers and neutral individuals. CONCLUSION: Medical maximizing-minimizing preferences in older women correspond with preferences for breast cancer treatment options that guidelines identify as potentially unnecessary. Increased awareness of patient-level variability in maximizing-minimizing preferences may be valuable in developing optimal intervention strategies to reduce utilization of low-value care.

Gaps in Online Breast Cancer Treatment Information for Older Women.

BACKGROUND: For women older than 70 years with early-stage breast cancer, the routine use of sentinel lymph node biopsy (SLNB) and adjuvant radiotherapy offers no overall survival benefit and may be perceived as undesirable by many women. National guidelines allow possible omission of these practices for older women. This study aimed to assess the availability of web-based educational materials targeting older women and their age-specific treatment recommendations. METHODS: The study systematically assessed the websites of the top 25 "Best Hospitals for Cancer" ranked by the U.S. News & World Report, as well as the websites of four prominent national cancer organizations. RESULTS: Websites for the leading cancer hospitals and national cancer organizations contain extremely limited information directed toward older patients with breast cancer. Both SLNB and adjuvant radiotherapy are described as treatments "typically," "most often," or "usually" used in combination with breast-conserving surgery without circumstances noted for possible omission. Specifically, no hospital website and only one national organization in this study included information on the recommendation to avoid routine SLNB. Only two hospitals and two national organizations included information suggesting possible omission of adjuvant radiotherapy for patients older than 70 years. CONCLUSION: The absence of online material for older patients with breast cancer represents a gap potentially contributing to overtreatment by framing SLNB and adjuvant radiotherapy as necessary. Informational resources available to women aged 70 years or older may aid in informed physician-patient communication and decision-making, which may reduce SLNB and adjuvant radiotherapy for patients who might opt out of these procedures if fully informed about them.