Cost-Effectiveness of Parathyroid Cryopreservation and Autotransplantation.

Importance: Delayed autotransplantation of cryopreserved parathyroid tissue (DACP) is the only surgical treatment for permanent postoperative hypoparathyroidism. Studies suggest that only a small minority of cryopreserved samples are ultimately autotransplanted with highly variable outcomes. For these reasons, many have questioned the economic utility of the process, although, to the authors' knowledge, this has never been formally studied. Objective: To report the clinical outcomes of parathyroid cryopreservation and DACP at a large academic institution and to determine the cost-effectiveness of this treatment. Design, Setting, and Participants: An institutional review board-approved, retrospective review of patients at a single institution who underwent DACP over a 17-year period was conducted with a median follow-up of 48.2 months. A forward-looking cost-utility analysis was then performed to determine the economic utility of cryopreservation/DACP vs usual care (monitoring and supplementation). Patients who had parathyroid tissue in cryopreserved storage between August 2005 to September 2022 at a single-center, academic, quaternary care center were identified. Exposure: Parathyroid cryopreservation and DACP. Main Outcomes and Measures: Graft functionality, clinical outcomes, and cost utility using a willingness-to-pay threshold of $100 000 per quality-adjusted life-year (QALY). Results: A total of 591 patients underwent cryopreservation. Of these, 10 patients (1.7%; mean [SD] age, 45.6 [17.9] years; 6 male [60%]) underwent DACP. A minority of autografts (2 [20%]) were subsequently fully functional, one-half (5 [50%]) were partially functional, and 3 (30%) were not functional. The cost-utility model estimated that at a large academic center over 10 years, the additional cost of 591 patients undergoing cryopreservation and 10 patients undergoing autotransplantation would be $618 791.64 (2022 dollars) and would add 8.75 QALYs, resulting in a cost per marginal QALY of $70 719.04, which is less than the common willingness-to-pay threshold of $100 000/QALY. Conclusions and Relevance: The reimplantation rate of cryopreserved tissue was low (<2%), but when implanted, autografts were at least partially functional 70% of the time. In the first-ever, to the authors' knowledge, formal cost analysis for this treatment, results of the current model suggest that cryopreservation and autotransplantation were cost-effective compared with the usual care for hypoparathyroidism at a large, academic institution. It is recommended that each surgical center consider whether the economic and logistical commitments necessary for cryopreservation are worthwhile for their individual needs.

Molecular characteristics of isthmus papillary thyroid cancers: Supporting evidence for unfavorable clinical behavior.

BACKGROUND: Previous studies demonstrate isthmus thyroid nodules are more likely to be malignant than lobar nodules. Additional data suggest that isthmus papillary thyroid cancers (PTCs) are more aggressive than lobar PTCs. We hypothesize that isthmus PTCs have a more unfavorable molecular profile. METHODS: The Cancer Genome Atlas (TCGA) database was queried to analyze clinical, mutation and gene expression data of isthmus PTCs compared to non-isthmus PTCs. RESULTS: We analyzed characteristics of 472 â€‹PTCs, including 19 isthmus PTCs. There were no significant differences between isthmus and non-isthmus PTC demographic and clinical variables or the frequency of RAS family, fusion driver, TERT, and tumor suppressor gene mutations. There was a trend towards increased BRAF mutations (68% vs 55%, p â€‹= â€‹0.28). A more aggressive gene expression profile was observed in isthmus PTC compared to lobar/multifocal PTC with differences in ERK score (19.4 vs 7.71, p â€‹< â€‹0.05) and TDS score (-0.58 vs 0.02, p â€‹< â€‹0.05). CONCLUSIONS: These results provide a possible molecular explanation for the more aggressive behavior reported in isthmus PTCs.

Total thyroidectomy is more cost-effective than radioactive iodine as an alternative to antithyroid medication for Graves' disease.

BACKGROUND: Patients with Graves' disease treated with radioactive iodine report worse quality of life than those treated by thyroidectomy. However, radioactive iodine is often selected due to lower risk of complications and lower cost. The objective of this study was to estimate the cost-effectiveness of radioactive iodine versus total thyroidectomy for treatment of Graves' disease. METHODS: A Markov decision-analytic model was created to simulate clinical outcomes and costs of medication-refractory Graves' disease treated with radioactive iodine or total thyroidectomy. Complication rates and utilities were derived from published data. Costs were extracted from national Medicare reimbursement rates. We conducted 1-way, 2-way, and probabilistic sensitivity analyses to identify factors that influence cost-effectiveness and reflect uncertainty in model parameters. The willingness-to-pay threshold was set at $100,000/quality-adjusted life-years. RESULTS: Total thyroidectomy yielded 23.6 quality-adjusted life-years versus 20.9 quality-adjusted life-years for radioactive iodine. The incremental cost-effectiveness ratio was $2,982 per quality-adjusted life-years, indicating that surgery is highly cost-effective relative to radioactive iodine. Surgery was more cost effective than radioactive iodine in 88.2% of model simulations. Sensitivity analyses indicate that the model outcomes are driven predominantly by posttreatment quality of life, with contributing effects from rates of treatment complications and the impact of these complications on quality of life. CONCLUSION: For patients with Graves' disease who either cannot tolerate or are refractory to antithyroid drugs, thyroidectomy is more cost-effective than radioactive iodine. Future research should validate reported differences in quality of life between these 2 treatment modalities.

The American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Secondary and Tertiary Renal Hyperparathyroidism.

OBJECTIVE: To develop evidence-based recommendations for safe, effective, and appropriate treatment of secondary (SHPT) and tertiary (THPT) renal hyperparathyroidism. BACKGROUND: Hyperparathyroidism is common among patients with chronic kidney disease, end-stage kidney disease, and kidney transplant. The surgical management of SHPT and THPT is nuanced and requires a multidisciplinary approach. There are currently no clinical practice guidelines that address the surgical treatment of SHPT and THPT. METHODS: Medical literature was reviewed from January 1, 1985 to present January 1, 2021 by a panel of 10 experts in SHPT and THPT. Recommendations using the best available evidence was constructed. The American College of Physicians grading system was used to determine levels of evidence. Recommendations were discussed to consensus. The American Association of Endocrine Surgeons membership reviewed and commented on preliminary drafts of the content. RESULTS: These clinical guidelines present the epidemiology and pathophysiology of SHPT and THPT and provide recommendations for work-up and management of SHPT and THPT for all involved clinicians. It outlines the preoperative, intraoperative, and postoperative management of SHPT and THPT, as well as related definitions, operative techniques, morbidity, and outcomes. Specific topics include Pathogenesis and Epidemiology, Initial Evaluation, Imaging, Preoperative and Perioperative Care, Surgical Planning and Parathyroidectomy, Adjuncts and Approaches, Outcomes, and Reoperation. CONCLUSIONS: Evidence-based guidelines were created to assist clinicians in the optimal management of secondary and tertiary renal hyperparathyroidism.

Treat Now or Treat Later: Comparative Effectiveness of Adjuvant Therapy in Resected Stage IIIA Melanoma.

BACKGROUND: Adjuvant therapy for most sentinel-node-positive (stage IIIA) melanoma may have limited clinical benefit for older patients given the competing risk of non-cancer death. The objective of this study is to model the clinical effect and cost of adjuvant therapy in stage IIIA melanoma across age groups. STUDY DESIGN: A Markov decision analysis model simulated the overall survival of patients with resected stage IIIA melanoma treated with adjuvant therapy vs observation. In the adjuvant approach, patients are modeled to receive adjuvant pembrolizumab (BRAF wild type) or dabrafenib/trametinib (BRAF mutant). In the observation approach, treatment is deferred until recurrence. Transition variables were derived from landmark randomized trials in adjuvant and salvage therapy. The model was analyzed for age groups spanning 40 to 89 years. The primary outcome was the number needed to treat (NNT) to prevent one melanoma-related death at 10 years. Cost per mortality avoided was estimated using Medicare reimbursement rates. RESULTS: Projections for NNT among BRAF wild type patients increased by age from 14.71 (age 40 to 44) to 142.86 (age 85 to 89), with patients in cohorts over the age of 75 having an NNT over 25. The cost per mortality avoided ranged from $2.75 million (M) (age 40 to 44) to $27.57M (age 85 to 89). Corresponding values for BRAF mutant patients were as follows: NNT 18.18 to 333.33; cost per mortality avoided ranged from $2.75M to $54.70M. CONCLUSION: Universal adjuvant therapy for stage IIIA melanoma is costly and provides limited clinical benefit in patients older than 75 years.

Low-Risk Papillary Thyroid Cancer: Treatment De-Escalation and Cost Implications.

INTRODUCTION: The American Thyroid Association (ATA) updated consensus guidelines in 2015 for radioactive iodine (RAI) and resection for low-risk papillary thyroid cancer. The objective of this study was to describe the evolution of institutional practice patterns and estimate the cost implications of these trends. MATERIALS AND METHODS: Patients with cT1-T2N0 papillary thyroid cancer were identified via an institutional tumor registry. Incidences of total thyroidectomy or RAI were tracked longitudinally using cumulative sum. Real-world costs for RAI and each surgical encounter were adjusted for inflation and standardized to national average costs from National Inpatient Sample cost data. RESULTS: Sixty-one patients met inclusion criteria between 2007 and 2018. Among these, 28 patients underwent total thyroidectomies and received RAI treatments based on criteria pre-dating the 2015 ATA guidelines. Cumulative sum revealed significant decreases in the rate of total thyroidectomy following May 2015 (15.8% versus 59.5%, P = 0.002) and RAI following March 2013 (3.0% versus 32.1%, P = 0.002). There were no locoregional recurrences in either period. The average cost savings attributable to these institutional practice changes was $1580 per patient. CONCLUSIONS: De-escalation in surgical and RAI utilization for low-risk papillary thyroid cancer according to 2015 ATA guidelines is associated with a substantial decrease in real-world costs.

The Antiresorptive Effect of GIP, But Not GLP-2, Is Preserved in Patients With Hypoparathyroidism-A Randomized Crossover Study.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are gut hormones secreted postprandially. In healthy humans, both hormones decrease bone resorption accompanied by a rapid reduction in parathyroid hormone (PTH). The aim of this study was to investigate whether the changes in bone turnover after meal intake and after GIP- and GLP-2 injections, respectively, are mediated via a reduction in PTH secretion. This was tested in female patients with hypoparathyroidism given a standardized liquid mixed-meal test (n = 7) followed by a peptide injection test (n = 4) using a randomized crossover design. We observed that the meal- and GIP- but not the GLP-2-induced changes in bone turnover markers were preserved in the patients with hypoparathyroidism. To understand the underlying mechanisms, we examined the expression of the GIP receptor (GIPR) and the GLP-2 receptor (GLP-2R) in human osteoblasts and osteoclasts as well as in parathyroid tissue. The GIPR was expressed in both human osteoclasts and osteoblasts, whereas the GLP-2R was absent or only weakly expressed in osteoclasts. Furthermore, both GIPR and GLP-2R were expressed in parathyroid tissue. Our findings suggest that the GIP-induced effect on bone turnover may be mediated directly via GIPR expressed in osteoblasts and osteoclasts and that this may occur independent of PTH. In contrast, the effect of GLP-2 on bone turnover seems to depend on changes in PTH and may be mediated through GLP-2R in the parathyroid gland. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Race, Ethnicity, and Clinical Outcomes in Hormone Receptor-Positive, HER2-Negative, Node-Negative Breast Cancer in the Randomized TAILORx Trial.

BACKGROUND: Black race is associated with worse outcomes in early breast cancer. We evaluated clinicopathologic characteristics, the 21-gene recurrence score (RS), treatment delivered, and clinical outcomes by race and ethnicity among women who participated in the Trial Assigning Individualized Options for Treatment. METHODS: The association between clinical outcomes and race (White, Black, Asian, other or unknown) and ethnicity (Hispanic vs non-Hispanic) was examined using proportional hazards models. All P values are 2-sided. RESULTS: Of 9719 eligible women with hormone receptor-positive, HER2-negative, node-negative breast cancer, there were 8189 (84.3%) Whites, 693 (7.1%) Blacks, 405 (4.2%) Asians, and 432 (4.4%) with other or unknown race. Regarding ethnicity, 889 (9.1%) were Hispanic. There were no substantial differences in RS or ESR1, PGR, or HER2 RNA expression by race or ethnicity. After adjustment for other covariates, compared with White race, Black race was associated with higher distant recurrence rates (hazard ratio [HR] = 1.60, 95% confidence intervals [CI] = 1.07 to 2.41) and worse overall survival in the RS 11-25 cohort (HR = 1.51, 95% CI = 1.06 to 2.15) and entire population (HR = 1.41, 95% CI = 1.05 to 1.90). Hispanic ethnicity and Asian race were associated with better outcomes. There was no evidence of chemotherapy benefit for any racial or ethnic group in those with a RS of 11-25. CONCLUSIONS: Black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy in the Trial Assigning Individualized Options for Treatment. Similar to Whites, Black women did not benefit from adjuvant chemotherapy if the 21-gene RS was 11-25. Further research is required to elucidate the basis for this racial disparity in prognosis.

Patient-Reported Cognitive Impairment Among Women With Early Breast Cancer Randomly Assigned to Endocrine Therapy Alone Versus Chemoendocrine Therapy: Results From TAILORx.

PURPOSE: Cancer-related cognitive impairment (CRCI) is common during adjuvant chemotherapy and may persist. TAILORx provided a novel opportunity to prospectively assess patient-reported cognitive impairment among women with early breast cancer who were randomly assigned to chemoendocrine therapy (CT+E) versus endocrine therapy alone (E), allowing us to quantify the unique contribution of chemotherapy to CRCI. METHODS: Women with a 21-gene recurrence score of 11 to 25 enrolled in TAILORX were randomly assigned to CT+E or E. Cognitive impairment was assessed among a subgroup of 552 evaluable women using the 37-item Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) questionnaire, administered at baseline, 3, 6, 12, 24, and 36 months. The FACT-Cog included the 20-item Perceived Cognitive Impairment (PCI) scale, our primary end point. Clinically meaningful changes were defined a priori and linear regression was used to model PCI scores on baseline PCI, treatment, and other factors. RESULTS: FACT-Cog PCI scores were significantly lower, indicating more impairment, at 3, 6, 12, 24, and 36 months compared with baseline for both groups. The magnitude of PCI change scores was greater for CT+E than E at 3 months, the prespecified primary trial end point, and at 6 months, but not at 12, 24, and 36 months. Tests of an interaction between menopausal status and treatment were nonsignificant. CONCLUSION: Adjuvant CT+E is associated with significantly greater CRCI compared with E at 3 and 6 months. These differences abated over time, with no significant differences observed at 12 months and beyond. These findings indicate that chemotherapy produces early, but not sustained, cognitive impairment relative to E, providing reassurance to patients and clinicians in whom adjuvant chemotherapy is indicated to reduce recurrence risk.

Clinical Outcomes in Early Breast Cancer With a High 21-Gene Recurrence Score of 26 to 100 Assigned to Adjuvant Chemotherapy Plus Endocrine Therapy: A Secondary Analysis of the TAILORx Randomized Clinical Trial.

Importance: A high 21-gene recurrence score (RS) by breast cancer assay is prognostic for distant recurrence of early breast cancer after local therapy and endocrine therapy alone, and for chemotherapy benefit. Objective: To describe clinical outcomes for women with a high RS who received adjuvant chemotherapy plus endocrine therapy in the TAILORx trial, a population expected to have a high distant recurrence rate with endocrine therapy alone. Design, Setting, and Participants: In this secondary analysis of data from a multicenter randomized clinical trial, 1389 women with hormone receptor-positive, ERBB2-negative, axillary node-negative breast cancer, and a high RS of 26 to 100 were prospectively assigned to receive adjuvant chemotherapy in addition to endocrine therapy. The analysis was conducted on May 12, 2019. Interventions: The adjuvant chemotherapy regimen was selected by the treating physician. Main Outcomes and Measures: Freedom from recurrence of breast cancer at a distant site, and freedom from recurrence, second primary cancer, and death (also known as invasive disease-free survival [IDFS]). Results: Among the 9719 eligible women, with a mean age of 56 years (range 23-75 years), 1389 (14%) had a recurrence score of 26 to 100, of whom 598 (42%) had an RS of 26 to 30 and 791 (58%) had an RS of 31 to 100. The most common chemotherapy regimens included docetaxel/cyclophosphamide in 589 (42%), an anthracycline without a taxane in 334 (24%), an anthracycline and taxane in 244 (18%), cyclophosphamide/methotrexate/5-fluorouracil in 52 (4%), other regimens in 81 (6%), and no chemotherapy in 89 (6%). At 5 years, the estimated rate of freedom from recurrence of breast cancer at a distant site was 93.0% (standard error [SE], 0.8%), freedom of recurrence of breast cancer at a distant and/or local regional site 91.0% (SE, 0.8%), IDFS 87.6% (SE, 1.0%), and overall survival 95.9% (SE, 0.6%). Conclusions and Relevance: The estimated rate of freedom from recurrence of breast cancer at a distant site in women with an RS of 26 to 100 treated largely with taxane and/or anthracycline-containing adjuvant chemotherapy regimens plus endocrine therapy in the prospective TAILORx trial was 93% at 5 years, an outcome better than expected with endocrine therapy alone in this population. Trial Registration: ClinicalTrials.gov identifier: NCT00310180.

Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer.

BACKGROUND: The use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known. METHODS: We performed a prospective trial involving 9427 women with hormone-receptor-positive, human epidermal growth factor receptor 2-negative, axillary node-negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger. RESULTS: The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (±SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7±1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3±2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2±3.3%). CONCLUSIONS: Clinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.).

Parathyroid-Targeted Overexpression of Regulator of G-Protein Signaling 5 (RGS5) Causes Hyperparathyroidism in Transgenic Mice.

The relationship between impaired calcium sensing, dysregulated parathyroid hormone (PTH) secretion, and parathyroid cell proliferation in parathyroid neoplasia is not understood. We previously reported that a GTPase activating protein, regulator of G-protein signaling 5 (RGS5) is overexpressed in a subset of parathyroid tumors associated with primary hyperparathyroidism (PHPT) and that RGS5 can inhibit signaling from the calcium-sensing receptor (CASR). In vivo, we found that RGS5-null mice have abnormally low PTH levels. To gain a better understanding of the potential role of RGS5 overexpression in parathyroid neoplasia and PHPT and to investigate whether inhibition of CASR signaling can lead to parathyroid neoplasia, we created and characterized a transgenic mouse strain overexpressing RGS5 specifically in the parathyroid gland. These mice develop hyperparathyroidism, bone changes reflective of elevated PTH, and parathyroid neoplasia. Further, expression of exogenous RGS5 in normal human parathyroid cells results in impaired signaling from CASR and negative feedback on PTH secretion. These results provide evidence that RGS5 can modulate signaling from CASR and support a role for RGS5 in the pathogenesis of PHPT through inhibition of CASR signaling. © 2019 American Society for Bone and Mineral Research.

Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer.

BACKGROUND: The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score. METHODS: We performed a prospective trial involving 10,273 women with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease-free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death). RESULTS: Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease-free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease-free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local-regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease-free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25. CONCLUSIONS: Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger. (Funded by the National Cancer Institute and others; TAILORx ClinicalTrials.gov number, NCT00310180 .).

Polyclonal origin of parathyroid tumors is common and is associated with multiple gland disease in primary hyperparathyroidism.

BACKGROUND: Parathyroid tumors are mostly considered monoclonal neoplasms, the rationale for focused parathyroidectomy in primary hyperparathyroidism. We reported that flow sorting parathyroid tumor cells and methylation-sensitive polymerase chain reaction (me-PCR) of polymorphic human androgen receptor gene and phosphoglycerate kinase gene alleles in deoxyribonucleic acid reveals that ≤35% of parathyroid tumors are polyclonal. We sought to confirm these findings and assess for clinical relevance. METHODS: Parathyroid tumors from 286 female primary hyperparathyroidism patients were analyzed for clonal status. Tumor clonal status was compared with clinical variables and operative findings. Statistical analysis was performed and significance was established at P < .05. RESULTS: In the study, 176 (62%) patients were informative for human androgen receptor gene and/or phosphoglycerate kinase gene. Assignment of clonal status was made in 119 (68%) tumors, of which 64 (54%) were monoclonal and 55 (46%) were polyclonal. Comparison of tumor clonal status to clinical variables in patients with complete operative data (N = 82) showed that while clinical features were the same between tumor types, patients with polyclonal tumors more often had multiple gland disease (risk ratio 4.066, confidence interval, 1.016-16.26; P = .039) potentially missed at unilateral neck exploration. CONCLUSION: This work confirms that primary hyperparathyroidism is often the result of polyclonal tumors and that parathyroid tumor clonal status may be associated with multiple gland disease.

Reporter gene assays for investigating GPCR signaling.

Luciferase-based assays are applied to evaluate various cellular processes due to their sensitivity and feasibility. The field of GPCR research has also benefited from this enzymatic reaction both in deorphanization campaigns and in delineation of the signaling pathways. Here, we describe the details of this assay in GPCR studies in 96-well format and will provide examples where the assay can show constitutive activity of an orphan GPCR and demonstrate the impact of cell type on the efficacy and potency of ligands.

Cytoplasmic Cyclin E Mediates Resistance to Aromatase Inhibitors in Breast Cancer.

Purpose: Preoperative aromatase inhibitor (AI) therapy has demonstrated efficacy in hormone receptor (HR)-positive postmenopausal breast cancer. However, many patients have disease that is either intrinsically resistant to AIs or that responds initially but develops resistance after prolonged exposure. We have shown that patients with breast tumors expressing the deregulated forms of cyclin E [low molecular weight forms (LMW-E)] have poor overall survival. Herein, we hypothesize that LMW-E expression can identify HR-positive tumors that are unresponsive to neoadjuvant AI therapy due to the inability of AIs to induce a cytostatic effect.Experimental Design: LMW-E was examined in breast cancer specimens from 58 patients enrolled in the American College of Surgeons Oncology Group Z1031, a neoadjuvant AI clinical trial. The mechanisms of LMW-E-mediated resistance to AI were evaluated in vitro and in vivo using an inducible model system of cyclin E (full-length and LMW-E) in aromatase-overexpressing MCF7 cells.Results: Breast cancer recurrence-free interval was significantly worse in patients with LMW-E-positive tumors who received AI neoadjuvant therapy, compared with those with LMW-E negative tumors. Upon LMW-E induction, MCF7 xenografts were unresponsive to letrozole in vivo, resulting in increased tumor volume after treatment with AIs. LMW-E expression overcame cell-cycle inhibition by AIs in a CDK2/Rb-dependent manner, and inhibition of CDK2 by dinaciclib reversed LMW-E-mediated resistance, whereas treatment with palbociclib, a CDK4/6 inhibitor, did not.Conclusions: Collectively, these findings suggest that cell-cycle deregulation by LMW-E mediates resistance to AIs and a combination of CDK2 inhibitors and AIs may be an effective treatment in patients with HR-positive tumors that express LMW-E. Clin Cancer Res; 23(23); 7288-300. ©2017 AACR.

Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer.

Significant endocrine therapy-resistant tumor proliferation is present in ≥20% of estrogen receptor-positive (ER+) primary breast cancers and is associated with disease recurrence and death. Here, we uncover a link between intrinsic endocrine therapy resistance and dysregulation of the MutL mismatch repair (MMR) complex (MLH1/3, PMS1/2), and demonstrate a direct role for MutL complex loss in resistance to all classes of endocrine therapy. We find that MutL deficiency in ER+ breast cancer abrogates CHK2-mediated inhibition of CDK4, a prerequisite for endocrine therapy responsiveness. Consequently, CDK4/6 inhibitors (CDK4/6i) remain effective in MutL-defective ER+ breast cancer cells. These observations are supported by data from a clinical trial where a CDK4/6i was found to strongly inhibit aromatase inhibitor-resistant proliferation of MutL-defective tumors. These data suggest that diagnostic markers of MutL deficiency could be used to direct adjuvant CDK4/6i to a population of patients with breast cancer who exhibit marked resistance to the current standard of care.Significance: MutL deficiency in a subset of ER+ primary tumors explains why CDK4/6 inhibition is effective against some de novo endocrine therapy-resistant tumors. Therefore, markers of MutL dysregulation could guide CDK4/6 inhibitor use in the adjuvant setting, where the risk benefit ratio for untargeted therapeutic intervention is narrow. Cancer Discov; 7(10); 1168-83. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1047.

Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance).

Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) -positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588).