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Boyce, Eric G., Yvonne Mai, and Christopher Pham. "Abaloparatide: Review of a Next-Generation Parathyroid Hormone Agonist." Annals of Pharmacotherapy 52, no. 5 (December 14, 2017): 462–72. http://dx.doi.org/10.1177/1060028017748649.
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Objective: To review the efficacy, safety, and economics of abaloparatide in the treatment of postmenopausal osteoporosis. Data Sources: PubMed (1966 to October 2017), Clinicaltrials.gov (October 2017), and Scopus (1970 to October 2017) were searched using abaloparatide, Tymlos, BA058, PTHrP 1-34 analog, and parathyroid hormone–related peptide 1-34 analog. Study Selection and Data Extraction: Human studies published in peer-reviewed publications in English were the primary sources for efficacy, safety, and economic data. Data Synthesis: In the 2 randomized, published clinical studies of 24 weeks and 18 months duration, bone mineral density changes were higher for abaloparatide (lumbar spine, 6.7%-11.2%; femoral head, 3.1%-3.2%; total hip, 2.6%-4.2%) compared with placebo (lumbar spine, 0.6%-1.6%; femoral head, −0.4% to 0.8%; total hip, −0.1% to 0.4%; P < 0.05) and compared with teriparatide in the 24-week study (total hip 2.6% vs +0.5%, P < 0.05). New vertebral and nonvertebral fractures occurred in 0.6% and 2.7% of patients on abaloparatide compared with 4.2% and 4.7% on placebo in the 18-month study ( P < 0.05). Abaloparatide appears to have a somewhat higher risk for adverse effects, discontinuation as a result of adverse effects, and serious or severe adverse effects than teriparatide, but teriparatide has a higher risk for hypercalcemia. Pharmacoeconomic modeling appears to favor abaloparatide if differences in efficacy and cost are maintained. Conclusion: Abaloparatide, which has less effect on osteoclasts, is an alternative to teriparatide in patients with postmenopausal osteoporosis who are at high risk for fractures or who have failed antiresorptive therapy based on initial clinical studies and economic modeling.
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Öberg, Kjell, and Steven W. J. Lamberts. "Somatostatin analogues in acromegaly and gastroenteropancreatic neuroendocrine tumours: past, present and future." Endocrine-Related Cancer 23, no. 12 (December 2016): R551—R566. http://dx.doi.org/10.1530/erc-16-0151.
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Acromegaly is a hormonal disorder that arises when the pituitary gland secretes excess growth hormone (GH), which in turn stimulates a concomitant increase in serum insulin-like growth factor 1 (IGF-1) levels. Gastroenteropancreatic neuroendocrine tumours (GEP-NET) constitute a heterogeneous group of tumours that can secrete serotonin and a variety of peptide hormones that may cause characteristic symptoms known as carcinoid syndrome or other symptoms and hormonal hypersecretion syndromes depending on the tumour’s site of origin. Current medical therapy for the treatment of acromegaly and GEP-NET involves the administration of somatostatin analogues that effectively suppress excess hormone secretion. After its discovery in 1979, octreotide became the first synthetic biologically stable somatostatin analogue with a short-acting formulation of octreotide introduced into clinical practice in the late 1980s. Lanreotide, another somatostatin analogue, became available in the mid-1990s initially as a prolonged-release formulation administered every 10 or 14 days. Long-acting release formulations of both octreotide (Sandostatin LAR and Novartis) and lanreotide (Somatuline Autogel, Ipsen), based on microparticle and nanoparticle drug-delivery technologies, respectively, were later developed, which allowed for once-monthly administration and improved convenience. First-generation somatostatin analogues remain one of the cornerstones of medical therapy in the management of pituitary and GEP-NET hormone hypersecretion, with octreotide having the longest established efficacy and safety profile of the somatostatin analogue class. More recently, pasireotide (Signifor), a next-generation multireceptor-targeted somatostatin analogue, has emerged as an alternative therapeutic option for the treatment of acromegaly. This review summarizes the development and clinical success of somatostatin analogues.
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Gomes, Jessica Ribeiro, Raphael Brandao Moreira, Matheus Bongers Alessandretti, and Marcelo Rocha De Sousa Cruz. "Next-generation sequencing (NGS) for personalized therapy in metastatic breast cancer: Selection of therapy and outcomes." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e23166-e23166. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23166.
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e23166 Background: Treatment for metastatic breast cancer (MBC) has been driven by hormone receptors, HER2 expressions or their absence. Resistance to therapy and progressive disease will occur and empirical chemotherapy lines usually are the next steps. We aim to analyze the role of next-generation sequencing (NGS) for a personalized therapy in metastatic breast cancer and its potential clinical benefit. Methods: We included patients diagnosed with MBC treated at Centro Oncologico Antonio Ermirio de Moraes – Brazil from April 2013 to December 2016. All patients had metastasis accessible for biopsy. The tumor tissue was stored in paraffin and then analyzed by NGS-based assay that identifies genomic alterations within 236 genes. Results: 19 patients with MBC were evaluated (10 triple-negative; 4 HER2-positive; 5 hormonal receptor positive/HER2-negative). The most frequent and relevant genomic alterations identified by NGS assay were in the following genes: 13 TP53 (68.4%); 4 ERBB2 (21%); 4 PTEN (21%); 4 FGFR (21%); 3 PIK3CA (15.8%); 2 BRCA (10.5%); 2 ATM (10.5%); 2 AKT (10.5%); 2 MYC (10.5%); 1 CCND1 (5.3%); and 1 KRAS (5.3%). The NGS assay was able to suggest further therapy in 16/19 patients (84%). The suggested therapies would not be an empirical option according to the cancer’s subtype in 12/16 patients (75%). Therapy could be personalized in nine patients, across multiple lines of therapies (median of 5th line, with a range of 1-14). Median PFS was 6 months, and 8/9 patients (90%) achieved an objective response with the treatment indicated by NGS. Therefore, the assay provided clinical benefit in 42% of patients. Conclusions: NGS panel identified potentially actionable alterations in the majority of patients with MBC (84%). The overall clinical benefit with use of NGS-based assay was 42%. Further studies are necessary to better evaluate the role of NGS for a personalized therapy in MBC.
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Payne, Forrest W., Bradley Ledden, and Greg Lamps. "Capabilities of Next-Generation Patch Pump: Improved Precision, Instant Occlusion Detection, and Dual-Hormone Therapy." Journal of Diabetes Science and Technology 13, no. 1 (May 24, 2018): 49–54. http://dx.doi.org/10.1177/1932296818776028.
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Insulin pumps allow patients to attain better blood glucose control with more lifestyle flexibility. Their size and cost, however, limit their usefulness. Current CSII pumps are bulky, intrusive, and expensive. SFC Fluidics is addressing these problems by developing a new type of wearable patch pump based on the patented electro-chemiosmotic (ECO) microfluidic pumping technology. This nonmechanical pumping technology allows accurate and precise delivery of very small amounts of insulin and/or other drugs, including concentrated insulin. The pump engine is small and can be made inexpensively from injection molded parts, allowing its use in a disposable or semidisposable pod format. In addition, a single ECO pump engine can be used to deliver two drugs through independent pathways. Other features of SFC Fluidics’ pod include latching safety valves that prevent accidental overdosing of insulin due to pressure changes and an instantaneous occlusion sensor that can immediately detect delivery failure at the first missed dose. These features allow for the development of a series of patch pumps that will offer users the benefit of CSII therapy in a more discreet and reliable patch pump form.
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Frolova, M. A., E. B. Glazkova, and M. B. Stenina. "Palbociclib in the first line combination hormone therapy of HER2- negative metastatic hormone-dependent breast cancer. Clinical follow-up." Medical Council, no. 10 (July 19, 2018): 158–60. http://dx.doi.org/10.21518/2079-701x-2018-10-158-160.
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According with the present-day ideas, sequential lines of hormone therapy including those in patients with visceral metastases and multiple lesions form the basis of the treatment of HER2-negative metastatic hormone-dependent breast cancer. These measures make it possible to exercise the long-term control of the disease and maintain a good quality of life. In recent years, the clinical practice comprises the next-generation drugs that potentiate the effect of hormone therapy. These include cyclindependent kinases 4/6 inhibitors. Palbociclib (Ibransa, Pfizer) is the first representative of this class approved in Russia for the treatment of disseminated hormone-dependent breast cancer. The PALOMA-2 study demonstrated the high efficacy of the palbociclib combined with letrozole as a first-line hormone therapy. In the palbociclib and letrozole combination arm, the median time to progression was 27,6 months compared to 14,5 months in the letrozole monotherapy arm (p <0,001). The presented clinical case demonstrates the possibility of long-term successful control of the disease using palbociclib combined with letrozole hormone therapy.
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Mayer, E. "Abstract ED08-02: Next generation therapeutics in hormone positive breast cancer: balancing efficacy and tolerability." Cancer Research 84, no. 9_Supplement (May 2, 2024): ED08–02—ED08–02. http://dx.doi.org/10.1158/1538-7445.sabcs23-ed08-02.
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Abstract The past several years have brought a wealth of new and emerging novel agents for the management of both early and advanced hormone repcetor positive breast cancer, including inhibitors of PIK3CA, mTOR, AKT, CDK4/6, PARP, as well as oral SERDs. These agents have significantly improved survival outcomes for many patients, but progress may come at the cost of specific and sometimes challeging side effects, whcih may threaten the ability to keep a patient on a therapy that is providing benefit. We will review a spectrum of agents, the expected side effect profiles, and strategies to mitigate toxicity and maximize therapeutic index. Citation Format: E. Mayer. Next generation therapeutics in hormone positive breast cancer: balancing efficacy and tolerability [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr ED08-02.
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Gaspard, Ulysse, Melanie Taziaux, Maud Jost, Sven O. Skouby, Rogerio A. Lobo, and Jean-Michel Foidart. "Estetrol (E4), the next generation hormone therapy (HT) for menopausal symptoms: phase 2b clinical trial results." Maturitas 124 (June 2019): 153. http://dx.doi.org/10.1016/j.maturitas.2019.04.122.
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Lv, Dan, Binliang Liu, Bo Lan, Lixi Li, Xiaoying Sun, and Fei Ma. "Clinical value of next-generation sequencing in endocrine therapy for advanced hormone receptor–positive/HER2-negative breast cancer." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 1062. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.1062.
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1062 Background: Acquired gene mutation is a major mechanism of resistance to endocrine therapy in hormone receptor (HR)-positive advanced breast cancer. Circulating tumor DNA (ctDNA) facilitates the current assessment of the genomic profile in patients with advanced cancer. We performed this clinical trial to determine the landscape of gene mutation before endocrine therapy, to search for molecular markers of endocrine therapy efficacy, and to explore the clinical value of ctDNA to guide precise endocrine therapy in patients with advanced breast cancer. Methods: We conducted an open-label, single-center, multicohort, prospective study. Patients were women with pathologically and immunohistochemically confirmed HR-positive/HER-2-negative patients with advanced breast cancer. Patients relapsed during or after adjuvant endocrine therapy or progressed after completing at least one previous line of treatment for advanced breast cancer. Patients were assigned to four parallel treatment cohortsmatched to mutations identified in ctDNA: 1) cohort A comprised patients with abnormal activation of PI3K/Akt/mTOR pathway signal, preferred mTOR inhibitor combined with endocrine therapy; 2) cohort B comprised patients with ESR1 mutation and who did not use fulvestrant before, preferred fulvestrant; 3) cohort C comprised patients with HER2 mutations, preferred pyrotinib combined with endocrine therapy; 4) cohort D comprised patients with no significant gene mutation, making treatment plan according to the actual clinical situation. If more than one mutation was identified, the priority of entry is cohorts C, cohorts A and cohort B. In the A-D cohort, patients who obey the treatment plan are the compliance group, and patients who do not obey the treatment plan are the violation group. The primary endpoints were progression-free survival (PFS), and the secondary endpoints included overall survival time (OS). Results: A total of 113 patients underwent NGS detection of ctDNA, and 84 patients were enrolled in the study. In all cohorts, combined median PFS was 4.9 months, and the median PFS in the compliance group was 3.0 months longer than in the violation group (6.03 vs 3.03 months, p = 0.0222, HR = 0.5743, 95%CI 0.3273-1.007). In cohort C, the median PFS was 11.1 months in the compliance group and 2.22 months in the violation group (p = 0.0067, HR = 0.1980, 95%CI 0.032-1.22). There was no significant difference in the median PFS between patients with and without compliance with the treatment protocol in cohort A and cohort B (p = 0.5054 and 0.7325, respectively). Conclusions: The study suggested that ctDNA detection may guide the optimal endocrine therapy strategy for patients with advanced breast cancer and achieve the benefit of progression free survival. NGS detection might distinguish patients with HER2 mutation and provide new treatment strategies. Clinical trial information: NCT03786575.
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Hempel, Dirk, Florian Ebner, Valeria Milani, Wolfgang Janni, Amelie De Gregorio, Andreas Gaumann, Zeljka Trepotec, Arun Garg, and Louisa Hempel. "Real-world data analysis of next generation sequencing and protein expression in metastatic breast cancer patients." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e13005-e13005. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e13005.
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e13005 Background: Next generation sequencing (NGS) together with protein expression analysis is back bone of molecularly targeted therapy in precision medicine. The present study shows the retrospective analysis of our experience with NGS using a panel of 324 genes in combination with protein expression in patients with metastatic breast cancer (mBC) over the last 18 months. The primary objective of this study was to analyze the prevalence of individual genetic alterations combined with protein expression to define potential targets for an individualized therapy. Methods: We analyzed 41 patients with advanced BC using solid tumor genomic profiling test. The test was used to detect clinically relevant genomic alterations (point mutations, indels, rearrangements, CNAs, tumor mutation burden (TMB) and microsatellite instability (MSI)) and to support the selection of appropriate targeted therapy. The protein expression (hormon receptors, ERBB2 and PDL1) of tumors was analyzed by immunohistochemistry (IHC). Results: The most common BC subtypes were HR+/ERBB2- (n = 20), followed by triple-negative (n = 15), and HER2+ BC (n = 9). 41 different genetic alterations were reported. Most patients had more than one genetic alteration (n = 27), as determined by NGS. The most common alterations were PIK3CA (n = 14), out of which 11 (78%) were hormone-receptor positive/ERBB2 negative. Conclusions: The NGS of mBC supports the decision for the most promising treatment option in 58,5% of our patients with a Tier I evidence. For an appropriate treatment decision it is necessary to evaluate gene alterations und protein expression of metastases in account. For an appropriate interpretation of rare gene alterations in mBC basket trials on basis of real world data are necessary. We founded the OnkoVision alliance to bring MTB into clinically routine and to identify appropriate patients for basket trials.
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Ligibel, Jennifer A., and Eric P. Winer. "The Aromatase Inhibitors as Adjuvant Therapy for Hormone Receptor-Positive Breast Cancer." Journal of the National Comprehensive Cancer Network 1, no. 2 (April 2003): 215–21. http://dx.doi.org/10.6004/jnccn.2003.0020.
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Adjuvant hormonal therapy has been shown to decrease the risk of breast cancer recurrence and overall mortality in patients with hormone receptor-positive breast cancer. Tamoxifen has been used in this setting for many years, both in premenopausal and postmenopausal patients. Tamoxifen is not devoid of toxicity, and attempts have been made to develop newer hormonal agents with better efficacy and less toxicity. The aromatase inhibitors have shown equivalent or superior efficacy to tamoxifen in the treatment of metastatic breast cancer, and efforts are underway to determine the role of these agents in early breast cancer. The ATAC trial recently showed that use of the third-generation aromatase inhibitor anastrozole in the adjuvant setting led to a modest improvement in relapse-free survival as compared with tamoxifen. Patients treated with anastrozole were also less likely to develop uterine cancer or experience a thromboembolic event. However, patients treated with anastrozole were more likely than those treated with tamoxifen to suffer a fracture or other musculosketal problem. An ASCO technology assessment panel reviewed the relevant data and issued a consensus statement regarding the use of aromatase inhibitors in the adjuvant setting. In general, the panel favored the continued use of tamoxifen as adjuvant hormonal therapy for most postmenopausal women. Within the next few years, further data from the ATAC trial and from other trials of aromatase inhibitors in the adjuvant setting should be available to guide treatment recommendations for this patient population.
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Andreev, D. A., and A. A. Zavyalov. "Cardiovascular safety of hormone therapy for prostate cancer." Cancer Urology 18, no. 3 (December 9, 2022): 85–91. http://dx.doi.org/10.17650/1726-9776-2022-18-3-85-91.
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Background. As of 2019, prostate cancer (PCa) is the second most common malignancy in men living in Russia (15.7 % of all cancer cases detected in 2019). Cardiovascular diseases, in particular atherosclerosis, are believed to be the second most frequent cause of death in PCa patients.Aim. To evaluate cardiovascular safety of hormone therapy for PCa on the example of gonadotropin releasing hormone (GnRH) agonists and antagonists (leuprolide and degarelix), second-generation antiandrogens (enzalutamide), and steroidogenesis inhibitors (abiraterone).Materials and methods. We analyzed the results of original studies assessing cardiovascular safety of hormone therapy in PCa patients published in 2020–2021 and indexed in PubMed. The results of other meta-analyses and systematic reviews were not included.The search for publications was performed using the PubMed database and the Google system. The following key words were used for searching: prostate cancer, cardiovascular risks, cardiovascular safety, outcomes, atherosclerosis, etc. We analyzed studies published between January 2020 and January 2022. Articles in English and Russian were selected manually; no filters were applied.Results. We examined the results of the latest and most relevant original studies assessing cardiovascular safety of key innovative hormone therapies for PCa. The majority of recent studies were based on routine clinical practice; they were registered in highly specialized cancer registers.Hormone therapy is associated with cardiotoxicity, which increases the risk of non-cancer related death in PCa patients. New, sometimes conflicting evidence is being constantly accumulated. This evidence suggests that the GnRH antagonist (degarelix) has a better cardiovascular safety profile than the GnRH agonist (leuprolide); enzalutamide is safer than abiraterone. Further search for prognostic biomarkers in PCa patients is needed.Conclusion. More high-quality studies analyzing adverse cardiovascular events in PCa patients conducted in routine clinical practice and registered in the online databases are the next stage to identify benefits of one antitumor drug over another. This will help to choose optimal hormone therapy algorithms for PCa patients and, therefore, increase their overall survival.
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Calcaterra, Valeria, Rossella Lamberti, Claudia Viggiano, Sara Gatto, Luigina Spaccini, Gianluca Lista, and Gianvincenzo Zuccotti. "Neonatal Dyshormonogenetic Goiter with Hypothyroidism Associated with Novel Mutations in Thyroglobulin and SLC26A4 Gene." Pediatric Reports 13, no. 2 (May 2, 2021): 210–15. http://dx.doi.org/10.3390/pediatric13020029.
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Congenital goiter is an uncommon cause of neck swelling and it can be associated with hypothyroidism. We discuss a case of primary hypothyroidism with goiter presenting at birth. Ultrasound showed the enlargement of the gland and thyroid function tests detected marked hypothyroidism. Genetic analysis via next generation sequencing (NGS) was performed finding two mutations associated with thyroid dyshormonogenesis: c.7813 C > T, homozygous in the exon 45 of the thyroglobulin gene (TG) and c.1682 G > A heterozygous in exon 15 of the SLC26A4 gene (pendrin). Sanger sequencing of parents’ DNA samples revealed that the first mutation (c.7813 C > T) was inherited from both of them, while the second one (c.1682 G > A) was inherited from the mother. Hormone replacement therapy was started, following which a gradual decrease in the size of the goiter was seen with the normalization of hormonal levels. Normal infant growth status and neurological development were recorded during follow-up. Neonatal dyshormonogenetic goiter with hypothyroidism may represent an unusual cause of neonatal neck mass. Early identification and hormone replacement therapy are crucial for a better neurodevelopmental outcome. Genetic analysis is mandatory in order to reach a specific diagnosis and to elucidate new patterns of thyroid disorder.
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Ades, Felipe, Dimitrios Zardavas, Ivana Bozovic-Spasojevic, Lina Pugliano, Debora Fumagalli, Evandro de Azambuja, Giuseppe Viale, Christos Sotiriou, and Martine Piccart. "Luminal B Breast Cancer: Molecular Characterization, Clinical Management, and Future Perspectives." Journal of Clinical Oncology 32, no. 25 (September 1, 2014): 2794–803. http://dx.doi.org/10.1200/jco.2013.54.1870.
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Gene expression profiling has reshaped our understanding of breast cancer by defining and characterizing four main intrinsic molecular subtypes: human epidermal growth factor receptor 2–enriched, basal-like, luminal A, and luminal B subtypes. Luminal B breast cancer has been reported to have lower expression of hormone receptors, higher expression of proliferation markers, and higher histologic grade than luminal A. It also exhibits worse prognosis and has a distinct profile of response to hormone therapy and chemotherapy. Although luminal cancers share similarities, the studies conducted in recent years using next-generation sequencing technology show that luminal A and B breast cancers should be perceived as distinct entities, with specific oncogenic drivers, rather than more proliferative varieties of luminal tumors. This review discusses the definition and molecular characterization of luminal B breast cancer and presents the available clinical evidence for chemotherapy and endocrine therapy patterns of response. It also provides an overview of ongoing research on molecularly targeted agents for this disease.
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Wani, Kashmira, Manasi Godbole, Brigid Jacob, Kylie Springer, and Vrushali Dabak. "Abstract PO5-15-08: Role of next-generation sequencing testing in metastatic breast cancer." Cancer Research 84, no. 9_Supplement (May 2, 2024): PO5–15–08—PO5–15–08. http://dx.doi.org/10.1158/1538-7445.sabcs23-po5-15-08.
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Abstract Background: With recent advances in therapy, patients with metastatic breast cancer have been living longer. Treatment has previously largely depended on the subtypes of breast cancer (ER/PR positive, HER2 positive, triple negative). In recent years, testing metastatic breast cancer samples for somatic and germline mutations has revealed additional therapeutic targets which could help patients further than standard therapeutic options. Recent evidence has demonstrated that targeted therapy may offer an advantage in overall survival in patients with metastatic breast cancer. However, data regarding the use of targeted therapy is still sparse and its overall impact on metastatic breast cancer patients needs to be further investigated. We wanted to study genomic testing in such patients and see how often it leads to new therapy recommendations beyond standard of care as we move towards the era of precision medicine. Methods: Patients who were diagnosed with metastatic breast cancer between 2015-2020 were screened and a total of 193 patients were identified. Baseline characteristics, treatment/outcome and NGS testing information was collected. Univariate two group comparisons were performed using t-tests for continuous variables, and using chi-square, or Fisher’s tests if cell counts were < 5 for categorical variables. Survival analysis for progression free survival (PFS) and overall survival (OS) were done using log rank tests. Results: Out of 193 patients, the majority (189) were female. There were 121 (62.7%) White patients, 69 (35.8%) Black patients, and 3 (1.6%) patients that were another race. 30.6 % of patients received next-generation sequencing (NGS) testing, 68.4% of patients did not, and 1% were unknown. Patients that received NGS testing were on average younger than those that did not receive NGS testing (53.24 years old vs 65.17 years old, respectively). Patients that received NGS testing were more likely to be premenopausal (p < .0001). Patients without NGS testing were more likely to die than those with NGS testing (p=.0327). There were no statistically significant differences observed in percentage of patients getting NGS testing done and whether patients were triple negative, HER2 positive with hormone receptor positive or negative, and HER2 negative with hormone receptor positive. As the year of metastatic breast cancer diagnosis advanced from 2015-2020, a high percentage of patients received NGS testing (i.e. 20% diagnosed in 2015 received NGS testing, whereas 50% diagnosed in 2020 received NGS testing). As the number of years between diagnosis and last follow-up increased, the probability of progression decreased for patients that had NGS testing done. Patients with NGS testing did better than those without NGS testing, but patients with no treatment change had the lowest probability of progression. Conclusion: On average, only 30% of patients are receiving NGS testing, however it is being done more often in recent years than ever before. There is a clear progression free survival benefit seen in patients who received NGS testing. It is interesting to note that those who did not receive any changes in treatment based on NGS testing have the lowest probability of progression, but overall survival was not different for any of the different groups studied. This could be related to the low number of patients with NGS testing in our analysis. Further studies are warranted to understand this association. Table. Summary of NGS testing data in various demographic categories There was a statistically significant difference in whether NGS testing was obtained or not and age, menopausal status and current status. There was no statistically significant difference in whether NGS testing was obtained or not and gender or race. Citation Format: Kashmira Wani, Manasi Godbole, Brigid Jacob, Kylie Springer, Vrushali Dabak. Role of next-generation sequencing testing in metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-15-08.
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Kudaravalli, Sriya, Neil Carleton, Margaret Q. Rosenzweig, and Julia Foldi. "Association between socioeconomic factors and utilization of next-generation sequencing in metastatic breast cancer." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): e13700-e13700. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.e13700.
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e13700 Background: Targeted therapies such as PI3K inhibitors have revolutionized the treatment of patients with metastatic breast cancer (MBC). Their selective use is enabled by next-generation sequencing (NGS) approaches, which help identify actionable tumor alterations. There may be socioeconomic disparities in NGS testing and NGS-guided treatment selection. This study aimed to investigate the role of socioeconomic status (SES) (race and area deprivation index [ADI]) among patients with MBC undergoing NGS. Methods: Our retrospective study included 418 adult patients (pts) with MBC treated at the Magee Women’s Cancer Center in Pittsburgh, PA between September 2016 and December 2022. Demographic information, including race and ADI, clinicopathologic information, and NGS results were collected. ADI based on zip code was derived utilizing Neighborhood Atlas. Scores range from 0-10 (higher score = higher deprivation), representing the census-based ranking of the ZIP code at the state level based on the composite of several factors, including income, education, employment, and housing quality. Descriptive statistics, chi-squared, and independent sample t tests were used. Multivariate logistic regression analysis was done to evaluate potential associations with receipt of NGS and NGS-directed therapy. Results: 89% of pts were non-Hispanic white (NHW); 11% were non-Hispanic black (NHB). A greater proportion of NHB pts were from higher ADI (6-10) neighborhoods (p=0.00001), suggesting lower SES. NHW pts were more likely to have hormone receptor (HR)+/human epidermal growth factor receptor (HER)2- tumors compared with NHB pts (p=0.022). 219 (52.4%) total pts had NGS tumor testing performed: 53% of NHW and 47.8% of NHB pts (p=0.511). 55.1% (102/185) of pts living in higher SES neighborhoods (ADI 1-5) and 50.2% (117/233) living in lower SES neighborhoods (ADI 6-10) received NGS testing (p=0.317). Of the 219 pts who got NGS testing, 62.6% (137) had a clinically actionable alteration identified, and of those, 46% (63) received corresponding targeted therapy. Of the 63 pts who received NGS-guided therapy, 88.9% were NHW and 11.1% were NHB (p=0.849), and 50.8% were from neighborhoods with ADI 1-5 and 49.2% were from neighborhoods with ADI 6-10 (p=0.571). In multivariate analysis including race, ADI, insurance status, year of MBC diagnosis, and tumor subtype, only tumor subtype (non-HR+/HER2- tumors) was significantly associated with a lower likelihood of both receiving NGS testing (p=0.032) and receiving NGS-directed therapy (p=0.001). Conclusions: There was a higher numerical rate of NGS testing and NGS-guided therapy initiation in NHW pts and pts from lower ADI (1-5 vs. 6-10) neighborhoods, but this did not reach statistical significance. Overall, in this single institution cohort limited by small numbers, there were no differences in NGS tumor testing based on race and SES.
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Matsumoto, Yoshitaka, Nobuyoshi Fukumitsu, Hitoshi Ishikawa, Kei Nakai, and Hideyuki Sakurai. "A Critical Review of Radiation Therapy: From Particle Beam Therapy (Proton, Carbon, and BNCT) to Beyond." Journal of Personalized Medicine 11, no. 8 (August 23, 2021): 825. http://dx.doi.org/10.3390/jpm11080825.
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In this paper, we discuss the role of particle therapy—a novel radiation therapy (RT) that has shown rapid progress and widespread use in recent years—in multidisciplinary treatment. Three types of particle therapies are currently used for cancer treatment: proton beam therapy (PBT), carbon-ion beam therapy (CIBT), and boron neutron capture therapy (BNCT). PBT and CIBT have been reported to have excellent therapeutic results owing to the physical characteristics of their Bragg peaks. Variable drug therapies, such as chemotherapy, hormone therapy, and immunotherapy, are combined in various treatment strategies, and treatment effects have been improved. BNCT has a high dose concentration for cancer in terms of nuclear reactions with boron. BNCT is a next-generation RT that can achieve cancer cell-selective therapeutic effects, and its effectiveness strongly depends on the selective 10B accumulation in cancer cells by concomitant boron preparation. Therefore, drug delivery research, including nanoparticles, is highly desirable. In this review, we introduce both clinical and basic aspects of particle beam therapy from the perspective of multidisciplinary treatment, which is expected to expand further in the future.
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McKay, Rana R., Felix Y. Feng, Alice Y. Wang, Christopher J. D. Wallis, and Kelvin A. Moses. "Recent Advances in the Management of High-Risk Localized Prostate Cancer: Local Therapy, Systemic Therapy, and Biomarkers to Guide Treatment Decisions." American Society of Clinical Oncology Educational Book, no. 40 (May 2020): e241-e252. http://dx.doi.org/10.1200/edbk_279459.
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High-risk prostate cancer accounts for approximately 15% of all prostate cancer diagnoses. Patients with high-risk disease have an increased risk of developing biochemical recurrence, metastases, and death from prostate cancer. As the optimal management of high-risk disease in patients with prostate cancer continues to evolve, the contemporary treatment paradigm is moving toward a multidisciplinary integrated approach of systemic and local therapy for patients with high-risk disease. The strategies for definitive, adjuvant, and salvage local treatment, including radical prostatectomy or radiation therapy, serve as the backbone of therapy for patients with localized disease. Systemic therapy decisions regarding use in combination with surgery, choice of therapy (hormone therapy, chemotherapy), and treatment duration continue to be refined. As more effective hormonal agents populate the treatment landscape for advanced prostate cancer, including abiraterone and next-generation antiandrogens, an opportunity is provided to explore these treatments in patients with localized disease in the hope of improving the long-term outcome for patients. Integration of innovative blood and tissue-based biomarkers to guide therapy selection for patients with high-risk disease is an area of active research. Contemporary studies are using such biomarkers to stratify patients and select therapies. In this review, we summarize contemporary evidence for local treatment strategies, systemic therapy options, and biomarkers in development for the management of high-risk prostate cancer in patients.
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Feldman, Rebecca, Michael Castro, Sandeep K. Reddy, and Charles E. Myers. "Taxane sensitivity markers in prostate cancer." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 285. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.285.
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285 Background: The results from the CHAARTED and STAMPEDE trials that docetaxel plus androgen-deprivation therapy (ADT) significantly improves survival over ADT alone among men with metastatic, hormone-sensitive and hormone-naïve prostate cancers, represents a potential practice-changing movement. Clinical data exist to support the role of various predictive markers for taxane response, including low or negative class III beta tubulin (TUBB3), positive transducin-like enhancer of split 3 (TLE3) and low or negative p-glycoprotein (PGP/ABCB1). We examined a database of molecularly-profiled prostate cancer patients for taxane sensitivity markers for insight into the mechanism behind the clinical effect of docetaxel. Methods: 348 patients with prostate cancer were included in the study and tested centrally at a CLIA laboratory (Caris Life Sciences, Phoenix, AZ). Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (C/FISH). Results: In all prostate cases tested, protein levels for taxane markers are: TLE3+ 58.6% (174/297), TUBB3 - 76.8% (228/297) and PGP – 89.9% (267/297). Combined rate of expression (TLE3+/TUBB3-/PGP-) is 41% (121/297), representing a subgroup of patients that may have best responses to taxane therapy. Taxane sensitivity markers by stage and AR status are shown in the table below. Conclusions: Taxane sensitivity markers are observed at a statistically significant higher frequency in AR-positive prostate cancer patients, providing a potential molecular hypothesis for the increased effectiveness of chemo-hormonal therapy observed in hormone-sensitive prostate cancers. A substantial number of both AR positive and negative patients have sub-optimal biomarker profile for taxane responsiveness highlighting an unmet need for on-going drug development in this disease. [Table: see text]
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Roadman, Daniel, David Cao, and Srinivas Vourganti. "Underutilization of best systemic therapy in patients with metastatic prostate cancer." Journal of Clinical Oncology 41, no. 6_suppl (February 20, 2023): 111. http://dx.doi.org/10.1200/jco.2023.41.6_suppl.111.
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111 Background: Advancement of treatment pathways in the management of metastatic prostate cancer (mPC) has identified newer systemic agents associated with survival advantage over androgen deprivation therapy (ADT) alone. Despite FDA approvals and guideline recommendations outlining standard of care (SOC) intensification of (ADT) with such additional systemic therapies such as docetaxel or novel hormonal therapies (NHT), these treatments are not being utilized uniformly by all practitioners. Our objective is to assess the utilization of such advanced therapies in patients with mPC and study differences in prescribing patterns. Methods: Between 2017 to present, we retrospectively identified all consecutive men with prostate cancer in a single health system. Electronic health record ICD code inquiries were used to identify patients. The population was further restricted utilizing diagnosis codes to include only those with metastatic prostate cancer and to exclude patients with second primary cancers. All treatment modalities and demographic information were analyzed to assess for prescribing patterns. Results: In total, 5,761 men had a diagnosis of prostate cancer. Exclusion criteria applied stepwise removed those with age <18 years (2 patients) and secondary malignancies (1046 patients), resulting in 4,713 men for analysis. Of these, 665 men were found to have mPC and included in the final cohort. Mean patient age was 70.3 ± 9.6 years. We found no statistically significant difference in SOC prescribing pattern based on race, ethnicity, insurance type, zip code, 2020 United States census household median income, nor year of treatment. There was, however, overall low utilization of intensification of ADT with docetaxel or NHT at 42%, with 58% of patients still being treated with only first generation antiandrogens or luteinizing hormone releasing hormone agonists. Conclusions: In a large health system, we found that next generation care can be provided independent of insurance payor profile, race, ethnicity, and socioeconomic status. However, despite guidelines to support newer systemic agents for patients with mPC, we continue to observe that it is underused in clinical practice. Additional studies are needed to identify potential clinician and patient barriers, as well as prescribing pattern failures that are limiting the implementation of evidence-based treatment beneficial to overall survival.
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Kang, Irene, Anishka D'souza, Darcy V. Spicer, Christy Ann Russell, Julie E. Lang, Maria Nelson, Howard Silberman, and Janice M. Lu. "Review of next generation sequencing outcomes in patients with metastatic breast cancer." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e12558-e12558. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e12558.
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e12558 Background: Among patients with newly diagnosed breast cancer in the US, 6-10% will have metastatic disease. With many treatment options to choose from, Next Generation Sequencing (NGS) is a technology that can potentially guide treatment. However studies on the clinical use of NGS are currently limited. Methods: We identified patients with metastatic breast cancer treated at Norris Comprehensive Cancer Center and Los Angeles County Medical Center who underwent NGS with FoundationOne, a clinical-grade NGS tool. Medical records were reviewed for genetic findings, tumor type, treatment outcomes and impact of NGS testing. Results: NGS data derived from FoundationOne testing were analyzed in 27 patients tested between 2013 and 2017. The most commonly occurring mutations were TP53 and PIK3 occurring in 29% of tested patients; followed by MYC, CDH1 and CCND1 (26% each). Clinical data were available for 26 patients:18 patients were hormone receptor (HR) positive Her2 negative, 6 were triple negative, one had HR positive Her2 positive disease, and one had adenoid cystic pathology. A median of 4 mutations per patient (range 0-13) were detected by NGS testing. Twenty-one of 27 patients (78%) were found to have clinically actionable mutations with a median of 1 clinically actionable mutation (range 0-3) per patient. Of these patients, 10 (47%) received treatment directed at their mutation. Five patients were treated on clinical trial as a result of AKT, PTEN or ERBB2 mutations. An additional two patients had received targeted treatments empirically before the time of NGS and three cases are intended for future use. Patients had received on average 5 lines of therapy (range 0-13) at time of study. Conclusions: In patients with metastatic breast cancer, NGS provides data that may drive clinical care. Potential benefits include more precise selection of treatment regimens as well as identifying benefit from drugs that are not yet standard of care in breast cancer. Here we report that clinically actionable mutations are found in a majority of patients tested. Further study is necessary to determine the utility of NGS in this population.
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Diaz Brinton, Roberta. "Minireview: Translational Animal Models of Human Menopause: Challenges and Emerging Opportunities." Endocrinology 153, no. 8 (July 9, 2012): 3571–78. http://dx.doi.org/10.1210/en.2012-1340.
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Increasing importance is placed on the translational validity of animal models of human menopause to discern risk vs. benefit for prediction of outcomes after therapeutic interventions and to develop new therapeutic strategies to promote health. Basic discovery research conducted over many decades has built an extensive body of knowledge regarding reproductive senescence across mammalian species upon which to advance animal models of human menopause. Modifications to existing animal models could rapidly address translational gaps relevant to clinical issues in human menopausal health, which include the impact of 1) chronic ovarian hormone deprivation and hormone therapy, 2) clinically relevant hormone therapy regimens (cyclic vs. continuous combined), 3) clinically relevant hormone therapy formulations, and 4) windows of opportunity and optimal duration of interventions. Modifications in existing animal models to more accurately represent human menopause and clinical interventions could rapidly provide preclinical translational data to predict outcomes regarding unresolved clinical issues relevant to women's menopausal health. Development of the next generation of animal models of human menopause could leverage advances in identifying genotypic variations in estrogen and progesterone receptors to develop personalized menopausal care and to predict outcomes of interventions for protection against or vulnerability to disease. Key to the success of these models is the close coupling between the translational target and the range of predictive validity. Preclinical translational animal models of human menopause need to keep pace with changes in clinical practice. With focus on predictive validity and strategic use of advances in genetic and epigenetic science, new animal models of human menopause have the opportunity to set new directions for menopausal clinical care for women worldwide.
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Lloyd, Maxwell R., Seth A. Wander, Erika Hamilton, Pedram Razavi, and Aditya Bardia. "Next-generation selective estrogen receptor degraders and other novel endocrine therapies for management of metastatic hormone receptor-positive breast cancer: current and emerging role." Therapeutic Advances in Medical Oncology 14 (January 2022): 175883592211136. http://dx.doi.org/10.1177/17588359221113694.
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Endocrine therapy (ET) is a pivotal strategy to manage early- and advanced-stage estrogen receptor-positive (ER+) breast cancer. In patients with metastatic breast cancer (MBC), progression of disease inevitably occurs due to the presence of acquired or intrinsic resistance mechanisms. ET resistance can be driven by ligand-independent, ER-mediated signaling that promotes tumor proliferation in the absence of hormone, or ER-independent oncogenic signaling that circumvents endocrine regulated transcription pathways. Estrogen receptor 1 ( ESR1) mutations induce constitutive ER activity and upregulate ER-dependent gene transcription, provoking resistance to estrogen deprivation and aromatase inhibitor therapy. The role ESR1 mutations play in regulating response to other therapies, such as the selective estrogen receptor degrader (SERD) fulvestrant and the available CDK4/6 inhibitors, is less clear. Novel oral SERDs and other next-generation ETs are in clinical development for ER+ breast cancer as single agents and in combination with established targeted therapies. Recent results from the phase III EMERALD trial demonstrated improved outcomes with the oral SERD elacestrant compared to standard anti-estrogen therapies in ER+ MBC after prior progression on ET, and other agents have shown promise in both the laboratory and early-phase clinical trials. In this review, we will discuss the emerging data related to oral SERDs and other novel ET in managing ER+ breast cancer. As clinical data continue to mature on these next-generation ETs, important questions will emerge related to the optimal sequence of therapeutic options and the genomic and molecular landscape of resistance to these agents.
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Nakanishi, Kazuho, Tomoaki Fukagawa, Takashi Yamada, and Shunji Suzuki. "Somatic gene mutations in malignant steroid cell tumours and response to multiple treatments." BMJ Case Reports 15, no. 12 (December 2022): e248486. http://dx.doi.org/10.1136/bcr-2021-248486.
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Malignant ovarian steroid cell tumours are a rare subgroup of sex cord-stromal tumours. There are no systematic reviews on the associated treatments, and little is known about their genomic profile. We describe a case of a pelvic malignant ovarian steroid cell tumour in a premenopausal woman in her 40s. She received cytoreductive surgery and six cycles of paclitaxel+carboplatin+bevacizumab. After recurrence, the tumour was surgically removed again, followed by radiation and hormone blockade therapy. Complete remission was achieved after treatment with bleomycin, etoposide and cisplatin. She remained in a platinum-sensitive relapse state and subsequently received maintenance therapy with olaparib. Since the tumour was initially refractory to treatment, tissue specimens were screened for gene mutations using a next-generation sequencing oncology panel and a somatic variant detection system, which revealed somatic gene mutations in ARID1A, PIK3CA, TERT and ATM, some of which are involved in DNA repair.
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Asih, Prita Riana, Anna M. Barron, Bin Ji, Andrew Katsifis, Filomena Mattner, Giuseppe Verdile, Veer Bala Gupta, Rob Trengove, and Ralph N. Martins. "P4-198: NOVEL TRANSLOCATOR PROTEIN (TSPO) LIGANDS FOR THE POTENTIAL TREATMENT OF ALZHEIMER'S DISEASE: A NEXT GENERATION ALTERNATIVE TO CONVENTIONAL HORMONE THERAPY." Alzheimer's & Dementia 10 (July 2014): P860—P861. http://dx.doi.org/10.1016/j.jalz.2014.05.1715.
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Savage, Martin Oswald, and Helen Louise Storr. "Balanced assessment of growth disorders using clinical, endocrinological, and genetic approaches." Annals of Pediatric Endocrinology & Metabolism 26, no. 4 (December 31, 2021): 218–26. http://dx.doi.org/10.6065/apem.2142208.104.
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Determining the pathogenesis of pediatric growth disorders is often challenging. In many cases, no pathogenesis is identified, and a designation of idiopathic short stature is used. The investigation of short stature requires a combination of clinical, endocrinological, and genetic evaluation. The techniques used are described, with equal importance being given to each of the 3 approaches. Clinical skills are essential to elicit an accurate history, family pedigree, and symptoms of body system dysfunction. Endocrine assessment requires hormonal determination for the diagnosis of hormone deficiency and initiation of successful replacement therapy. Genetic analysis has added a new dimension to the investigation of short stature and now uses next-generation sequencing with a candidate gene approach to confirm probable recognizable monogenic disorders and exome sequencing for complex phenotypes of unknown origin. Using the 3 approaches of clinical, endocrine, and genetic probes with equal status in the hierarchy of investigational variables provides the clinician with the highest chance of identifying the correct causative pathogenetic mechanism in a child presenting with short stature of unknown origin.
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Kanao, Kent, Takayuki Takahashi, Yuta Umezawa, Takashi Okabe, Go Kaneko, Suguru Shirotake, Koshiro Nishimoto, and Masafumi Oyama. "Efficacy of abiraterone acetate for high-risk hormone-naïve metastatic prostate cancer: A comparison with combined androgen blockade therapy with bicalutamide and androgen deprivation therapy alone." PLOS ONE 17, no. 10 (October 20, 2022): e0276081. http://dx.doi.org/10.1371/journal.pone.0276081.
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Background The treatment landscape for men with metastatic hormone-naïve prostate cancer (mHNPC) has dramatically changed with the approval of next-generation anti-androgen drugs. We compared the treatment efficacy of abiraterone with that of combined androgen blockade (CAB) therapy and androgen deprivation therapy (ADT) alone in men with high-risk mHNPC. Methods In total, 146 Japanese men with high-risk mHNPC were retrospectively analyzed. As initial hormonal therapy, 30, 83, and 33 men were treated with ADT plus abiraterone (ABI group), ADT plus bicalutamide (CAB group), and ADT alone (ADT group), respectively. Treatment efficacy was compared using time to castration resistance (TTCR) and prostate-specific antigen (PSA) response among the groups. Propensity score matching analysis was also performed to adjust for baseline differences. Results The median (95% confidence interval [CI]) TTCR in the ABI, CAB, and ADT groups were not reached, 10.7 (7.6–13.8) months and 11.0 (7.9–12.4) months, respectively, and it was significantly longer in the ABI group than in the other groups (p = 0.0012, p = 0.0008). In propensity score matching analysis, the median TTCR was also significantly longer in the ABI group than in the other groups (hazard ratio [HR], 0.47; 95% CI, 0.22–0.98; p = 0.010; HR, 0.32; 95% CI, 0.12–0.85; p = 0.004). The number of men who achieved PSA levels ≤0.2 ng/mL after propensity score matching were significantly higher in the ABI group than in the other groups. Conclusions Our results provide important evidence regarding the superiority of abiraterone over CAB therapy and ADT alone for initial treatment for men with newly diagnosed mHNPC.
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Patrikidou, Anna, Thomas Zilli, Giulia Baciarello, Safae Terisse, Zineb Hamilou, and Karim Fizazi. "Should androgen deprivation therapy and other systemic treatments be used in men with prostate cancer and a rising PSA post-local treatments?" Therapeutic Advances in Medical Oncology 13 (January 2021): 175883592110518. http://dx.doi.org/10.1177/17588359211051870.
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Biochemical recurrence is an evolving space in prostate cancer, with increasing multidisciplinary involvement. Androgen deprivation therapy has shown proof of its value in complementing salvage radiotherapy in high-risk biochemical relapsing patients; ongoing trials aim to further refine this treatment combination. As systemic treatments, and notably next-generation androgen receptor targeted agents, have moved towards early hormone-sensitive and non-metastatic stages, the prostate specific antigen (PSA)-relapse disease stage will be undoubtedly challenged by future evidence from such ongoing clinical trials. With the use of modern imaging and newer molecular technologies, including integration of tumoral genomic profiling and liquid biopsies in risk stratification, a path towards a precision oncology-focused approach will become a reality to guide in the future decisions for patients with a diagnosis of biochemical recurrence.
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Kirilova, L. G., O. O. Miroshnikov, O. E. Abaturov, N. V. Medvedovska, Yu G. Antipkin, and N. Y. Bondarenko. "Modern treatment of epileptic encephalopathies in young children: improvement of precision medicine." CHILD`S HEALTH 18, no. 5 (September 17, 2023): 329–37. http://dx.doi.org/10.22141/2224-0551.18.5.2023.1610.
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Background. Treatment of epileptic seizures in young children, especially with epileptic encephalopathies (EE), is a difficult task, which is impossible in modern conditions without the use of a personified (precision) therapy. The diagnostic algorithm for EE must include genetic examination by the next-generation sequencing, which makes it possible to prescribe targeted therapy depending on the genetic etiology of the disorder. The article presents the results of own research on the effectiveness and approaches to targeted therapy of genetic epileptic encephalopathies in young children. Materials and methods. Fifty-eight children aged 0–3 years with clinical manifestations of epileptic encephalopathies, onset of seizures in the first year of life and diagnosed genetic etiology were included in the study. Pathogenic variants in genes associated with the development of epileptic seizures were identified in all children using the next-generation sequencing. The study included assessment of neurological status, history collection, evaluation of semiology and seizure type, development and screening for autism spectrum disorders at the age of 18 and 24 months, video-electroencephalography during night sleep, magnetic resonance imaging of the brain, assessment of antiepileptic treatment received by the child. Results. Of 58 children with EE who were prescribed antiepileptic drugs, 10 (17.2 %) received monotherapy, 40 patients (69 %) received combined therapy with two anticonvulsants, and 8 children (13.8 %) — combined therapy with three or more anticonvulsants. Levetiracetam (31 patients), valproic acid salt preparations (20 cases), topiramate (11 children) and vigabatrin (10 cases) were most used antiepileptic drugs. In all examined patients with EE, we used schemes of targeted (personalized) antiepileptic therapy focused on the genetic etiology of the disorder. In children with tuberous sclerosis caused by mutations in the TSC1 and TSC2 genes, vigabatrin (50–150 mg/kg per day) was included in the antiepileptic therapy and showed efficacy in 75.0 % (9/12) of children with infantile spasms. Corticosteroids (adrenocorticotropic hormone or prednisone) were additionally included in the treatment regimen and showed effectiveness in 66.7 % of cases (4/6). In children with mutations in SCN1A gene, combined therapy including valproic acid, topiramate and clobazam, or valproic acid with levetiracetam and corticosteroids was used, which showed effectiveness in reducing the frequency of seizures in 100 % of cases. Conclusions. Epileptic encephalopathies are a heterogeneous group of genetic disorders in young children that are difficult to treat and often have a malignant course. Since standard antiepileptic drugs are often insufficiently effective in epileptic encephalopathies, the use of targeted therapy drugs and alternative treatments such as hormone therapy are extremely important. The goal of treatment for epileptic encephalopathies is not only to control seizures, but also to prevent the development of neurological and cognitive deficits and restore lost functions.
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Labarta, José I., Paul Dimitri, Matthew Keiser, Ekaterina Koledova, and Octavio Rivera-Romero. "Evaluating the Usefulness and Ease of Use of a Next-Generation–Connected Drug Delivery Device for Growth Hormone Therapy: Qualitative Study of Health Care Professionals’ Perceptions." JMIR Human Factors 10 (August 2, 2023): e46893. http://dx.doi.org/10.2196/46893.
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Background Digital solutions targeting children’s health have become an increasingly important element in the provision of integrated health care. For the treatment of growth hormone deficiency (GHD), a unique connected device is available to facilitate the delivery of recombinant human growth hormone (r-hGH) by automating the daily injection process and collecting injection data such that accurate adherence information is available to health care professionals (HCPs), caregivers, and patients. The adoption of such digital solutions requires a good understanding of the perspectives of HCPs as key stakeholders because they leverage data collection and prescribe these solutions to their patients. Objective This study aimed to evaluate the third generation of the easypod device (EP3) for the delivery of r-hGH treatment from the HCP perspective, with a focus on perceived usefulness and ease of use. Methods A qualitative study was conducted, based on a participatory workshop conducted in Zaragoza, Spain, with 10 HCPs experienced in the management of pediatric GHD from 7 reference hospitals in Spain. Several activities were designed to promote discussion among participants about predefined topics based on the Technology Acceptance Model and the Unified Theory of Acceptance and Use of Technology to provide their perceptions about the new device. Results Participants reported 2 key advantages of EP3 over previous easypod generations: the touch screen interface and the real-time data transmission functionality. All participants (10/10, 100%) agreed that the new device should be part of a digital health ecosystem that provides complementary functionalities including data analysis. Conclusions This study explored the perceived value of the EP3 autoinjector device for the treatment of GHD by HCPs. HCPs rated the new capabilities of the device as having substantial improvements and concluded that it was highly recommendable for clinical practice. EP3 will enhance decision-making and allow for more personalized care of patients receiving r-hGH.
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Iyer, Janaki, Arvind Hariharan, Uyen Minh Nha Cao, Crystal To Tam Mai, Athena Wang, Parisa Khayambashi, Bich Hong Nguyen, Lydia Safi, and Simon D. Tran. "An Overview on the Histogenesis and Morphogenesis of Salivary Gland Neoplasms and Evolving Diagnostic Approaches." Cancers 13, no. 15 (August 3, 2021): 3910. http://dx.doi.org/10.3390/cancers13153910.
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Salivary gland neoplasms (SGN) remain a diagnostic dilemma due to their heterogenic complex behavior. Their diverse histomorphological appearance is attributed to the underlying cellular mechanisms and differentiation into various histopathological subtypes with overlapping fea-tures. Diagnostic tools such as fine needle aspiration biopsy, computerized tomography, magnetic resonance imaging, and positron emission tomography help evaluate the structure and assess the staging of SGN. Advances in molecular pathology have uncovered genetic patterns and oncogenes by immunohistochemistry, fluorescent in situ hybridization, and next–generation sequencing, that may potentially contribute to innovating diagnostic approaches in identifying various SGN. Surgical resection is the principal treatment for most SGN. Other modalities such as radiotherapy, chemotherapy, targeted therapy (agents like tyrosine kinase inhibitors, monoclonal antibodies, and proteasome inhibitors), and potential hormone therapy may be applied, depending on the clinical behaviors, histopathologic grading, tumor stage and location, and the extent of tissue invasion. This review delves into the molecular pathways of salivary gland tumorigenesis, highlighting recent diagnostic protocols that may facilitate the identification and management of SGN.
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Fizazi, Karim, Donald Charles Vile, Zheng Hong Chen, Christian Heinrich Poehlein, Jelena Todoric, and Christian Gratzke. "CYP11A1 inhibitor MK-5684 versus next-generation hormonal agent (NHA) switch in patients with metastatic castration-resistant prostate cancer (mCRPC) after 1 prior NHA: Phase 3 MK-5684-004 study." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): TPS5114. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.tps5114.
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TPS5114 Background: Activating androgen receptor (AR) somatic mutation is a known mechanism of resistance to AR-directed therapies in mCRPC, and it may permit continued hormone dependence. Upstream targeting of androgen biosynthesis may provide a therapeutic advantage over available AR-directed therapies in patients with mCRPC. MK-5684 (ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), a catalyst of the first and rate-limiting step of steroid biosynthesis. Thus, MK-5684 has the potential to suppress the production of all steroid hormones and precursors that may activate the AR signaling pathway. MK-5684 demonstrated antitumor activity in patients with heavily pretreated mCRPC, especially in those with AR ligand binding domain (AR-LBD) mutations, in the phase 1/2 CYPIDES study. The efficacy and safety of MK-5684 in patients with molecularly unselected mCRPC after 1 prior NHA will be evaluated in the randomized, open-label, phase 3 MK-5684-004 study (NCT06136650). Methods: Eligible patients have mCRPC unselected for AR-LBD mutations that progressed during androgen deprivation therapy ≤6 months before screening and during or after 1 NHA for hormone-sensitive prostate cancer (HSPC) or nonmetastatic CRPC for ≥8 weeks (≥14 weeks with bone progression). Prior NHA + docetaxel for HSPC is permitted if patients received ≤6 cycles of docetaxel without radiographic disease progression. Approximately 1500 patients (AR-LBD mutation–positive, 375 patients; AR-LBD mutation–negative, 1125 patients) will be randomly assigned 1:1 to receive MK-5684 5 mg PO BID + dexamethasone 1.5 mg and fludrocortisone 0.1 mg PO QD or abiraterone acetate 1000 mg PO QD + prednisone 5 mg PO BID (if prior enzalutamide/darolutamide/apalutamide) or enzalutamide 160 mg PO QD (if prior abiraterone). Randomization will be stratified by metastasis (bone only/liver/other), AR-LBD mutation status (positive/negative), and prior docetaxel for HSPC (yes/no). Treatment will continue until unacceptable toxicity, radiographic disease progression (verified per Prostate Cancer Working Group 3 [PCWG3]–modified RECIST v1.1 by BICR), or other discontinuation criteria are met. Tumor assessments will be performed every 8 weeks through week 24, then every 12 weeks thereafter. Dual primary end points are radiographic PFS per PCWG3-modified RECIST v1.1 by BICR and OS in patients with AR-LBD mutation–positive and –negative disease, separately. Secondary end points include time to initiation of first subsequent anticancer therapy or death; ORR and DOR per PCWG3-modified RECIST v1.1 by BICR; time to pain progression; time to prostate-specific antigen (PSA) progression; PSA response rate; time to first symptomatic skeletal-related event; and safety and tolerability. Recruitment is ongoing. Clinical trial information: NCT06136650 .
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Hay, I. D., and G. G. Klee. "Linking medical needs and performance goals: clinical and laboratory perspectives on thyroid disease." Clinical Chemistry 39, no. 7 (July 1, 1993): 1519–24. http://dx.doi.org/10.1093/clinchem/39.7.1519.
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Abstract Diagnosis and management of thyroid disease benefit substantially from close interactions between clinicians and laboratorians. Clinicians desire reliable tests for diagnosis and management of both hypothyroidism and thyrotoxicosis. Traditionally, multitiered testing has been used, beginning with an index of free thyroxine concentration, which, if abnormal, has been followed by basal thyrotropin (TSH) measurements (for hypothyroidism) or thyrotropin-releasing hormone-stimulated TSH measurements (for thyrotoxicosis). Improvements in analytical methods for TSH have made it practical to use basal TSH measurements in serum as the first-line test for thyroid disease. However, performance guidelines are needed, because not all TSH assays work well in this role. The performance guidelines developed by the American Thyroid Association are reviewed to illustrate how they help to assure consistent analytical testing. Further improvements in TSH assays (third- and fourth-generation assays), which support measurements down to 0.01 mlU/L and 0.001 mIU/L, may provide additional advantages for classifying thyrotoxic patients and monitoring thyroxine-suppressive therapy in patients with thyroid cancer. The potential advantages of these newer assays are illustrated with case examples. Additional analytical performance monitors are proposed to help ensure that these next-generation TSH assays meet the expanded clinical needs.
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McKay, Rana R., Wanling Xie, Rosina Lis, Huihui Ye, Zhenwei Zhang, Quoc-Dien Trinh, Steven Lee Chang, et al. "Results of a phase II trial of neoadjuvant abiraterone + prednisone+ enzalutamide + leuprolide (APEL) versus enzalutamide + leuprolide (EL) for patients with high-risk localized prostate cancer (PC) undergoing radical prostatectomy (RP)." Journal of Clinical Oncology 36, no. 6_suppl (February 20, 2018): 79. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.79.
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79 Background: Patients with high-risk PC have an increased risk of recurrence and mortality despite therapy. Abiraterone, a CYP17 inhibitor, and enzalutamide, a next generation anti-androgen, have demonstrated improved overall survival in metastatic PC. In this multicenter randomized phase II trial, we evaluate the impact of second generation hormone therapy on RP pathologic outcomes. Methods: Eligible patients had biopsy Gleason score ≥4+3=7, PSA >20 ng/mL or cT3 disease (by prostate MRI). Lymph node were require to be <20 mm. Patients were randomized 2:1 to APE:EL for 6 cycles (24 weeks) followed by RP. All RPs underwent central pathology review. The primary endpoint was the rate of pathologic complete response (pCR) or minimum residual disease (MRD, tumor ≤5 mm). Secondary endpoints include PSA response, surgical staging at RP, positive margin rate, and safety. Results: 75 patients were enrolled at four sites: DFCI/BWH (n=55), BIDMC (n=11), UW (n=5), JHU (n=4). Median age was 62 years. Most patients had NCCN high-risk disease [n=66, 88%; cT3 n=21 (28%), Gleason 8-10 n=59 (79%), PSA >20 ng/mL n=17 (23%)]. All patients completed 6 cycles followed by RP. Median PSA nadir was 0.03 and 0.02 ng/mL and time to nadir was 3.7 and 4.6 months in the APEL and EL arms, respectively. The combined pCR or MRD rate was 30% (n=15/50) in the APEL arm and 16% (n=4/25) in the EL arm. The response difference was 14% (80% CI -3%-30%, p=0.263). 15 patients (14 in APEL; 1 in EL) had grade 3 adverse events (AEs). The most common grade 3 AEs were hypertension (n=7) and ALT increase (n=5). No grade 4-5 AEs occurred. Conclusions: Neoadjuvant hormone therapy plus RP in men with high-risk PC resulted in favorable pathologic responses (≤5 mm residual tumor) in 16-30% with a trend towards improved pathologic outcomes with APEL and acceptable safety profile. Follow-up is necessary to evaluate the impact of therapy on recurrence rates. Clinical trial information: NCT02268175. [Table: see text]
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Yakou, Fumiyoshi, Hirotsugu Suwanai, Takuya Ishikawa, Mariko Itou, Jumpei Shikuma, Takashi Miwa, Hiroyuki Sakai, et al. "A Novel Homozygous Mutation of Thyroid Peroxidase Gene Abolishes a Disulfide Bond Leading to Congenital Hypothyroidism." International Journal of Endocrinology 2020 (August 30, 2020): 1–8. http://dx.doi.org/10.1155/2020/9132372.
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Congenital hypothyroidism (CH) is the most prevalent congenital endocrine disorder and causes mental retardation. A male Japanese patient with first cousin marriage parents was diagnosed as CH at 10 months. He was born before introduction of mass screening for CH. With continuous thyroid hormone replacement therapy, normal thyroid hormone status was maintained until adulthood. Genetic screening of next-generation sequencing was performed at the age of 52 years, and we identified a new homozygous thyroid peroxidase (TPO) gene mutation (GRCh38.p13, chromosome 2 at position 1493997, c.1964 G>T, p.Cys655Phe). TPO is an important enzyme to produce thyroid hormone. As demonstrated by a homology analysis of TPO proteins among different species, cysteine 655 residue is highly conserved, suggesting an important role in maintaining TPO function and structure. An in silico study with three-dimensional structure of the novel mutation was performed and suggested that the mutation abolished disulfide bond between cysteines at positions 598 and 655. An in vitro functional analysis using HEK293 cells revealed that TPO activity of the mutant was significantly impaired compared with that of the wild type. Furthermore, study of immunohistochemistry showed that localization of TPO in cells did not differ between the wild type and the mutant. In conclusion, this single disulfide bond loss mutation of a new TPO homozygous mutation, p.Cys655Phe, reduced TPO activity and caused congenital hypothyroidism without affecting subcellular localization of TPO proteins.
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Schwartzberg, Lee S., and Lesli A. Kiedrowski. "Olaparib in hormone receptor-positive, HER2-negative metastatic breast cancer with a somatic BRCA2 mutation." Therapeutic Advances in Medical Oncology 13 (January 2021): 175883592110069. http://dx.doi.org/10.1177/17588359211006962.
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The oral poly(adenosine diphosphate-ribose) polymerase inhibitor olaparib is approved for the treatment of patients with human epidermal growth factor 2-negative (HER2−) metastatic breast cancer (mBC) and a germline breast cancer susceptibility gene (BRCA) mutation who have been treated with chemotherapy. This case report describes a 63-year-old postmenopausal woman with somatic BRCA2-mutated mBC who responded to olaparib treatment following multiple prior lines of therapy. The patient presented in January 2012 with locally advanced, hormone receptor-positive (HR+), HER2− BC which, despite initial response to neoadjuvant chemotherapy, recurred as bone disease in February 2014, and subsequently skin (June 2016) and liver (October 2016) metastases. A comprehensive 592-gene next-generation sequencing panel (Caris Life Sciences), performed on a skin biopsy, detected a pathogenic frameshift mutation in BRCA2 (H3154fs, c.9460delC), which was not identified in a 28-gene hereditary cancer germline analysis (Myriad Genetics, Inc.), and was therefore considered to be a somatic mutation. In January 2017, cell-free DNA (cfDNA) analysis (Guardant Health, Inc.) confirmed the BRCA2 H3154fs mutation in plasma. After several lines of chemotherapy and endocrine therapy, deriving clinical benefit from eribulin and capecitabine, the disease progressed by October 2017, and olaparib (300 mg orally twice daily) was initiated in January 2018. By April 2018, the liver lesions had shrunk by 80% and a >90% response in multiple skin lesions was noted. Clinical response was maintained for 8 months, followed by progression in the skin in September 2018. Biopsy of recurrent lesions revealed a novel BRCA2 mutation, E3152del (c.9455_9457delAGG), predicted to restore the open reading frame and presumably the mechanism of resistance to olaparib. Further likely resistance mutations were noted in subsequent cfDNA analyses. This case demonstrated a clinical response with olaparib as a later-line therapy for HR+, HER2− mBC with a somatic BRCA2 mutation.
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Collins, Denis M., Neil T. Conlon, Srinivasaraghavan Kannan, Chandra S. Verma, Lisa D. Eli, Alshad S. Lalani, and John Crown. "Preclinical Characteristics of the Irreversible Pan-HER Kinase Inhibitor Neratinib Compared with Lapatinib: Implications for the Treatment of HER2-Positive and HER2-Mutated Breast Cancer." Cancers 11, no. 6 (May 28, 2019): 737. http://dx.doi.org/10.3390/cancers11060737.
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An estimated 15–20% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2/ERBB2/neu). Two small-molecule tyrosine kinase inhibitors (TKIs), lapatinib and neratinib, have been approved for the treatment of HER2-positive (HER2+) breast cancer. Lapatinib, a reversible epidermal growth factor receptor (EGFR/ERBB1/HER1) and HER2 TKI, is used for the treatment of advanced HER2+ breast cancer in combination with capecitabine, in combination with trastuzumab in patients with hormone receptor-negative metastatic breast cancer, and in combination with an aromatase inhibitor for the first-line treatment of HER2+ breast cancer. Neratinib, a next-generation, irreversible pan-HER TKI, is used in the US for extended adjuvant treatment of adult patients with early-stage HER2+ breast cancer following 1 year of trastuzumab. In Europe, neratinib is used in the extended adjuvant treatment of adult patients with early-stage hormone receptor-positive HER2+ breast cancer who are less than 1 year from the completion of prior adjuvant trastuzumab-based therapy. Preclinical studies have shown that these agents have distinct properties that may impact their clinical activity. This review describes the preclinical characterization of lapatinib and neratinib, with a focus on the differences between these two agents that may have implications for patient management.
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Lee, Seung Ryeol, Tae Ho Lee, Seung-Hun Song, Dong Suk Kim, Kyung Hwa Choi, Jae Ho Lee, and Dae Keun Kim. "Update on genetic screening and treatment for infertile men with genetic disorders in the era of assisted reproductive technology." Clinical and Experimental Reproductive Medicine 48, no. 4 (December 1, 2021): 283–94. http://dx.doi.org/10.5653/cerm.2021.04476.
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A genetic etiology of male infertility is identified in fewer than 25% of infertile men, while 30% of infertile men lack a clear etiology, resulting in a diagnosis of idiopathic male infertility. Advances in reproductive genetics have provided insights into the mechanisms of male infertility, and a characterization of the genetic basis of male infertility may have broad implications for understanding the causes of infertility and determining the prognosis, optimal treatment, and management of couples. In a substantial proportion of patients with azoospermia, known genetic factors contribute to male infertility. Additionally, the number of identified genetic anomalies in other etiologies of male infertility is growing through advances in whole-genome amplification and next-generation sequencing. In this review, we present an up-to-date overview of the indications for appropriate genetic tests, summarize the characteristics of chromosomal and genetic diseases, and discuss the treatment of couples with genetic infertility by microdissection-testicular sperm extraction, personalized hormone therapy, and in vitro fertilization with pre-implantation genetic testing.
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Plachy, Lukas, Petra Dusatkova, Klara Maratova, Lenka Petruzelkova, Dana Zemkova, Lenka Elblova, Petra Kucerova, et al. "NPR2 Variants Are Frequent among Children with Familiar Short Stature and Respond Well to Growth Hormone Therapy." Journal of Clinical Endocrinology & Metabolism 105, no. 3 (January 28, 2020): e746-e752. http://dx.doi.org/10.1210/clinem/dgaa037.
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Abstract Context The C-type natriuretic peptide receptor encoded by the NPR2 gene is a paracrine regulator of the growth plate; heterozygous NPR2 variants cause short stature with possible presence of different signs of bone dysplasia. To date, the effect of growth hormone (GH) treatment has been described in a few individuals with NPR2 gene variants with inconsistent results. Objectives To identify NPR2 gene variants among children with familial short stature (FSS) and to describe their phenotype, including GH treatment response. Design, Settings and Patients Out of 747 patients with short stature treated with GH in a single center, 87 with FSS met the inclusion criteria (pretreatment height ≤ –2 standard deviation in both the patient and the shorter parent, unknown genetic etiology). Next-generation sequencing methods were performed to search for NPR2 gene variants. The results were evaluated using the American College of Medical Genetics and Genomics guidelines. The GH treatment response (growth velocity improvement and height standard deviation score development over the first 5 years of treatment) was evaluated. Results In 5/87 children (5.7%), a (likely) pathogenic variant in the NPR2 gene was identified (p.Ile558Thr [in 2], p.Arg205*, p.Arg557His, p.Ser603Thr). Two children had disproportionate short-limbed short stature, 1 a dysplastic 5th finger phalanx. The growth velocity in the first year of GH treatment accelerated by 3.6 to 4.2 cm/year; the height improved by 1.2 to 1.8 SD over 5 years of treatment. Conclusions NPR2 gene variants cause FSS in a significant proportion of children. Their GH treatment response is promising. Studies including final height data are necessary to assess the long-term efficacy of this therapy.
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Dai, Hao, Dechuang Jiao, Xuhui Guo, Jianghua Qiao, anfang Li, Zhenduo Lu, Xiuchun Chen, Chengzheng Wang, Min Yan, and Zhenzhen Liu. "Abstract 6439: Next-generation sequencing based detection of HER2 copy number predicts pathological response to neoadjuvant therapy in HER2 positive breast cancer." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6439. http://dx.doi.org/10.1158/1538-7445.am2024-6439.
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Abstract Purpose: Achieving pathologic complete response (pCR) following neoadjuvant chemotherapy is associated with better prognosis for HER2 positive breast cancer. However, clinical and biological heterogeneity of HER2 positive disease significantly affect prognosis and treatment response. Early prediction of treatment benefit could enable tailored anti-HER2 therapy. Next-generation sequencing (NGS) based genomic tests including copy number (CN) detection are widely used in breast cancer patients. We aim to evaluate the association of HER2 copy number detected by NGS with pCR rate of HER2 positive breast cancer after neoadjuvant chemotherapy. Methods: HER2 positive breast cancer patients underwent neoajuvant chemotherapy in Henan Cancer Hospital From January 2022 to March 2023 were included in the study. Pretreatment tumour specimens were subjected to pan-cancer 1021-gene panel genomic sequencing. Copy number of HER2 was obtained from the panel. Copy number of >=4 was classified as HER2 amplified and HER2 copy number <4 was classified as HER2 non-amplified. All patients underwnt definitive surgery after receieveing neoadjuvant chemotherapy containing taxanes, trastuzumab and pertuzumab. pCR was defined as pathological stage ypT0/Tis ypN0. Results: In total, 299 HER2 positive breast cancer patients were eligible for the analysis. 87 were classified as HER2 non-amplified (29.1%) by copy number and 212 patients were classified as amplified group (70.9%). The HER2 non-amplified group tends to have a higher proportion of hormone receptor positive (HR+) patients (71.3% vs. 50.5%, p=0.002). Other clinicopathological parameters were well distributed between the groups. 91.3% of patients in HER2 amplified group had strong positive HER2 expression (IHC 3+), while only 10.5% of patients in HER2 non-amplified group had HER2 expression of IHC 3+. Patients with HER2 IHC 3+ had a PCR rate of 75.8% and Patients with HER2 IHC 2+ had a pCR rate of 20.0% (20.0% vs. 75.8% p<0.001). Patients in the amplified group had a pCR rate of 76.9% and pCR rate of the non-amplified group was12.6% (12.6% vs. 76.9% p<0.001). In a multivariable logistic regression with HER2 copy number by NGS, HR status and HER2 IHC, the HER2 copy number predicted pCR rate independently of HER2 IHC and HR status. Conclusions: NGS based detection of HER2 copy number could predict response to neoadjuvant therapy in HER2 positive patients. The discordance between IHC/FISH and NGS based detection of HER2 amplification may reflect HER2 heterogeneity. HER2 heterogeneity promotes resistance to anti-HER2 therapy. Noval antibody-drug conjugates (ADC) with bystander effect, such as Trastuzumab deruxtecan, have shown anti-tumor effect even in HER2 low expression tumors. Thus, prospective study is needed to optimize anti-HER2 therapy for patients with HER2 heterogeneity. Citation Format: Hao Dai, Dechuang Jiao, Xuhui Guo, Jianghua Qiao, anfang Li, Zhenduo Lu, Xiuchun Chen, Chengzheng Wang, Min Yan, Zhenzhen Liu. Next-generation sequencing based detection of HER2 copy number predicts pathological response to neoadjuvant therapy in HER2 positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6439.
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Yoon, Seokhyun, Hye Sung Won, Keunsoo Kang, Kexin Qiu, Woong June Park, and Yoon Ho Ko. "Hormone Receptor-Status Prediction in Breast Cancer Using Gene Expression Profiles and Their Macroscopic Landscape." Cancers 12, no. 5 (May 5, 2020): 1165. http://dx.doi.org/10.3390/cancers12051165.
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The cost of next-generation sequencing technologies is rapidly declining, making RNA-seq-based gene expression profiling (GEP) an affordable technique for predicting receptor expression status and intrinsic subtypes in breast cancer patients. Based on the expression levels of co-expressed genes, GEP-based receptor-status prediction can classify clinical subtypes more accurately than can immunohistochemistry (IHC). Using data from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA BRCA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets, we identified common predictor genes found in both datasets and performed receptor-status prediction based on these genes. By assessing the survival outcomes of patients classified using GEP- or IHC-based receptor status, we compared the prognostic value of the two methods. We found that GEP-based HR prediction provided higher concordance with the intrinsic subtypes and a stronger association with treatment outcomes than did IHC-based hormone receptor (HR) status. GEP-based prediction improved the identification of patients who could benefit from hormone therapy, even in patients with non-luminal breast cancer. We also confirmed that non-matching subgroup classification affected the survival of breast cancer patients and that this could be largely overcome by GEP-based receptor-status prediction. In conclusion, GEP-based prediction provides more reliable classification of HR status, improving therapeutic decision making for breast cancer patients.
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Lin, Li, Mengting Li, Jingsi Luo, Pin Li, Shasha Zhou, Yu Yang, Ka Chen, et al. "A High Proportion of Novel ACAN Mutations and Their Prevalence in a Large Cohort of Chinese Short Stature Children." Journal of Clinical Endocrinology & Metabolism 106, no. 7 (February 19, 2021): e2711-e2719. http://dx.doi.org/10.1210/clinem/dgab088.
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Abstract Context Aggrecan, encoded by the ACAN gene, is the main proteoglycan component in the extracellular cartilage matrix. Heterozygous mutations in ACAN have been reported to cause idiopathic short stature. However, the prevalence of ACAN pathogenic variants in Chinese short stature patients and clinical phenotypes remain to be evaluated. Objective We sought to determine the prevalence of ACAN pathogenic variants among Chinese short stature children and characterize the phenotypic spectrum and their responses to growth hormone therapies. Patients and Methods Over 1000 unrelated short stature patients ascertained across China were genetically evaluated by next-generation sequencing–based test. Result We identified 10 novel likely pathogenic variants and 2 recurrent pathogenic variants in this cohort. None of ACAN mutation carriers exhibited significant dysmorphic features or skeletal abnormities. The prevalence of ACAN defect is estimated to be 1.2% in the whole cohort; it increased to 14.3% among those with advanced bone age and to 35.7% among those with both advanced bone age and family history of short stature. Nonetheless, 5 of 11 ACAN mutation carries had no advanced bone age. Two individuals received growth hormone therapy with variable levels of height SD score improvement. Conclusion Our data suggest that ACAN mutation is 1 of the common causes of Chinese pediatric short stature. Although it has a higher detection rate among short stature patients with advanced bone age and family history, part of affected probands presented with delayed bone age in Chinese short stature population. The growth hormone treatment was moderately effective for both individuals.
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Craig, Amaranta, Annelise M. Wilhite, Sharon Wu, Joanne Xiu, Gina Mantia-Smaldone, Enrique Hernandez, Jubilee Brown, and Nathaniel L. Jones. "Exploring molecular profiles and survival in hormone receptor-positive uterine serous carcinoma." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 5579. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.5579.
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5579 Background: Hormone receptor (HR) positivity has been reported as a good prognostic indicator in endometrial cancer. This study investigated estrogen receptor (ER) and progesterone receptor (PR) positivity as indicators of platinum response and improved survival in uterine serous carcinoma (USC), and determined differences in molecular profiles between these tumors and hormone receptor negative tumors. Methods: Tumor profiling was done with immunohistochemistry (IHC), next generation sequencing (NGS), and whole transcriptome sequencing (WTS). PD-L1 expression was determined by IHC using SP-142 (cut-off >1%). Microsatellite instability (MSI) status was evaluated with IHC and NGS, and tumor mutational burden (TMB) by totaling somatic mutations per tumor (high if > 10 mutations/ MB). Immune-cell fraction was determined with QuantiSeq. We used insurance claims data to calculate Kaplan-Meier estimates for overall survival (OS). Statistical significance was determined with chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons. Results: 2806 USC tumors were available for molecular profiling with 717 HR+/966 HR-, 1559 ER+/1059 ER- and 805 PR+/1809 PR-. Median OS for HR+ patients was longer than patients who were HR- regardless of treatment (1152 v 797 days; hazard ratio 0.68, 95% CI 0.58-0.80, p < 0.01). This OS benefit of HR positivity remained for patients receiving platinum therapy (1134 v 889 days; hazard ratio 0.75, 95% CI 0.58-0.98, p < 0.01). HR+ status trended towards improved OS in those treated with hormone therapy (407 vs 771 days, hazard ratio 0.78, 95% CI 0.59-1.02, p = 0.07). In addition to increased androgen receptor expression (54.2 vs 6.2%, p = < 0.001), PTEN mutations were more common in the HR+ group (10.3 vs 5.1%, p = 0.016). This resulted in in more frequent alterations of the PI3K pathway when compared to HR- tumors 64.5 vs 52.2%, p = < 0.001). PD-L1, TMB, and MSI status were similar between the two cohorts. Checkpoint inhibitor gene expression was notable for higher IDO expression in the HR+ group, but lower CD80, CD86, HAVCR2, IFNG, and PDC1 expression. The immune micro-environment was notable for less B-cells and M1 macrophages, but more M2 macrophages. Breaking the ER and PR positive cohort down to individual expression of each gene resulted in similar OS and molecular findings. Conclusions: HR positivity is associated with improved survival in allcomers with USC and those treated with platinum therapy, and there was a trend to improved OS with hormone therapy. More data is needed to determine if HR status is a prognostic marker for IO treatment response. This cohort had a distinct molecular profile compared to HR- tumors.
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Sisman, Yagmur, Lau Kræsing Vestergaard, Douglas Nogueira Perez de Oliveira, Tim Svenstrup Poulsen, Tine Henrichsen Schnack, Claus Høgdall, and Estrid Høgdall. "Potential Targeted Therapies in Ovarian Cancer." Pharmaceuticals 15, no. 11 (October 26, 2022): 1324. http://dx.doi.org/10.3390/ph15111324.
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Background: We aimed to identify somatic pathogenic and likely pathogenic mutations using next-generation sequencing (NGS). The mutational findings were held against clinically well-described data to identify potential targeted therapies in Danish patients diagnosed with high-grade serous ovarian cancer (HGSC). Methods: We characterized the mutational profile of 128 HGSC patients. Clinical data were obtained from the Danish Gynecological Database and tissue samples were collected through the Danish CancerBiobank. DNA was analyzed using NGS. Results: 47 (37%) patients were platinum-sensitive, 32 (25%) partially platinum-sensitive, 35 (27%) platinum-resistant, and three (2%) platinum-refractory, while 11 (9%) patients did not receive chemotherapy. Overall, 27 (21%) had known druggable targets. Twelve (26%) platinum-sensitive patients had druggable targets for PARP inhibitors: one for tyrosine kinase inhibitors and one for immunotherapy treatment. Eight (25%) partially platinum-sensitive patients had druggable targets: seven were eligible for PARP inhibitors and one was potentially eligible for alpesilib and hormone therapy. Seven (20%) platinum-resistant patients had druggable targets: six (86%) were potentially eligible for PARP inhibitors, one for immunotherapy, and one for erdafitinib. Conclusions: PARP inhibitors are the most frequent potential targeted therapy in HGSC. However, other targeted therapies remain relevant for investigation according to our mutational findings.
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Hofmann, Sven, Kathrin Bellmann-Sickert, and Annette G. Beck-Sickinger. "Chemical modification of neuropeptide Y for human Y1 receptor targeting in health and disease." Biological Chemistry 400, no. 3 (February 25, 2019): 299–311. http://dx.doi.org/10.1515/hsz-2018-0364.
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AbstractAs a very abundant neuropeptide in the brain and widely distributed peptide hormone in the periphery, neuropeptide Y (NPY) appears to be a multisignaling key peptide. Together with peptide YY, pancreatic polypeptide and the four human G protein-coupled receptor subtypes hY1R, hY2R, hY4R and hY5R it forms the NPY/hYR multiligand/multireceptor system, which is involved in essential physiological processes as well as in human diseases. In particular, NPY-induced hY1R signaling plays a central role in the regulation of food intake and stress response as well as in obesity, mood disorders and cancer. Thus, several hY1R-preferring NPY analogs have been developed as versatile tools to unravel the complex NPY/hY1R signaling in health and disease. Further, these peptides provide basic lead structures for the development of innovative drugs. Here, the current research is summarized focusing on the development of differently sized hY1R-preferring NPY analogs as well as their advances with respect to hY1R profiling, potential therapeutic applications and targeted cancer imaging and therapy. Finally, major limitations and innovative strategies for next generation hY1R-preferring NPY analogs are addressed.
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Spring, Laura, Andrzej Niemierko, Dejan Juric, Mark Zangardi, Elizabeth Abraham, Dora Dias-Santagata, Leif W. Ellisen, et al. "Tumor genomics and response to CDK 4/6 inhibitors for patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 1046. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.1046.
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1046 Background: The combination of endocrine therapy with a cyclin-dependent kinase (CDK) 4/6 inhibitor, such as palbociclib, has changed the treatment paradigm of HR+ MBC, particularly as 1stline therapy. However, there are no predictive biomarkers at present, and little is known about the impact of tumor genomics on outcomes. For example, mutations in TP53 could impact the ability of p53 to negatively regulate p21, thereby promoting cell cycle progression despite CDK 4/6 inhibition. The aim of this study was to evaluate the association between tumor genomics, particularly PIK3CA and TP53 mutations, and response to CDK 4/6 inhibitors in HR+ MBC. Methods: All HR+/HER2- MBC patients at our institution receiving a CDK 4/6 inhibitor in the second line or beyond were identified. Tumor genomics were analyzed utilizing the institutional tumor genotyping next generation sequencing (NGS) assay known as “Snapshot-NGS assay” on DNA isolated from the tumor, covering key oncogenic driver mutations and tumor suppressor genes. The log-rank test was used for statistical analysis. Results: A total of 83 patients with HR+/HER2- MBC were identified, of which 61 had available tumor genotyping results available (52 metastatic specimens). The median line of therapy was three. Median progression-free survival (PFS) on CDK 4/6 inhibitor-based therapy, as second line or beyond, was 9.2 months (mo) overall. No significant difference in PFS was seen among patients with PIK3CA (n = 31) mutations (7.1 vs. 9.7 mo; p = 0.28) or with any alteration in the PI3K/Akt/mTOR (n = 36) pathway (8.2 vs. 9.3 mo; p = 0.40). The presence of a p53 mutation (n = 9) or complex tumor genomics (n = 14) demonstrated a trend towards shorter PFS (5.5 vs. 9.2 mo; 5.5 vs. 9.5 mo, respectively), although statistical significance was not reached due to small numbers (p = 0.76; p = 0.31). In a multivariable analysis adjusting for age and prior lines of therapy, similar results were observed. Conclusions: This study suggests patients with HR+ MBC harboring p53 mutations or complex tumor genomics may experience shorter PFS on CDK 4/6 inhibitor-based therapy in the second line and beyond, and these novel findings require validation in additional studies.
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Park, Jisun, Eun Young Joo, Myung Ji Yoo, Su-Jin Kim, Woori Jang, and Ji-Eun Lee. "Clinical efficacy of multigene panels in the management of congenital hypothyroidism with gland in situ." Medicine 103, no. 29 (July 19, 2024): e38976. http://dx.doi.org/10.1097/md.0000000000038976.
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Congenital hypothyroidism (CHT) is a diverse condition with various genetic etiologies. This study aimed to investigate the utility of next-generation sequencing (NGS) analysis in guiding treatment decisions and predicting prognosis for CHT patients with gland in situ (GIS). A retrospective analysis was conducted on 33 CHT patients with GIS who underwent NGS analysis at a single institution between 2018 and 2023. Patients were classified as having permanent (PCH), transient congenital hypothyroidism, or ambiguous congenital hypothyroidism (ACH) CHT based on their response to levothyroxine discontinuation at 3 years of age. Among the 33 patients, genetic variants were identified in 26, with the most prevalent variants found in DUOX2 (26.92%), TSHR (30.77%), TG (19.35%), and DUOXA2 (19.23%). Patients with high initial thyroid-stimulating hormone levels (>50 mIU/L) and low free thyroxine levels (<0.89 ng/dL) at diagnosis tended to have compound heterozygous or homozygous variants in DUOX2, DUOXA2, and TG, and were more likely to develop PCH. In contrast, patients with heterozygous variants in these genes often exhibited ACH. TSHR variants were associated with diverse clinical manifestations, ranging from PCH to ACH, and were more common in patients with initial thyroid-stimulating hormone levels <50 mIU/L. The study highlights the potential utility of NGS analysis in predicting the clinical course and guiding treatment decisions for CHT patients with GIS. Genetic analysis may aid in determining the appropriate duration of levothyroxine therapy and monitoring strategies, particularly in cases where traditional clinical indicators are inconclusive.
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Keup, Corinna, Vinay Suryaprakash, Markus Storbeck, Oliver Hoffmann, Rainer Kimmig, and Sabine Kasimir-Bauer. "Longitudinal Multi-Parametric Liquid Biopsy Approach Identifies Unique Features of Circulating Tumor Cell, Extracellular Vesicle, and Cell-Free DNA Characterization for Disease Monitoring in Metastatic Breast Cancer Patients." Cells 10, no. 2 (January 21, 2021): 212. http://dx.doi.org/10.3390/cells10020212.
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Dynamics of mRNA from circulating tumor cells (CTCs), mRNA from extracellular vesicles (EVs), and cell-free DNA (cfDNA) were assessed to examine the relevance of a longitudinal multi-parametric liquid biopsy strategy. Eighteen milliliters of blood was drawn from 27 hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) patients at disease progression and at two subsequent radiologic staging time points. CTC mRNA and EV mRNA were analyzed using multi-marker qPCR, and cfDNA was analyzed using targeted next-generation sequencing (NGS). The presence of ERBB2 or ERBB3 overexpression signals in CTCs significantly correlated with disease progression (87% specificity, 36% sensitivity, p-value = 0.023), and the presence of either ERBB3 signals in CTCs or EVs or cfDNA variants in ERBB3 also showed a significant association with progressive MBC. Fluctuations during treatment were detected in the EV fraction with the appearance of hitherto undetected ERCC1 signals correlating with progressive disease (97% specificity, 18% sensitivity, p-value = 0.030). Allele frequency development of ESR1 and PIK3CA variants detected at subsequent staging time points could be used as a predictor for therapy success and, importantly, might help guide therapy decisions. The three analytes, each with their own unique features for disease monitoring, were shown to be complementary, underlining the usefulness of the longitudinal multi-parametric liquid biopsy approach.
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Conteduca, Vincenza, Giorgia Gurioli, Nicole Brighi, Cristian Lolli, Giuseppe Schepisi, Chiara Casadei, Salvatore Luca Burgio, et al. "Plasma Androgen Receptor in Prostate Cancer." Cancers 11, no. 11 (November 4, 2019): 1719. http://dx.doi.org/10.3390/cancers11111719.
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The therapeutic landscape of prostate cancer has expanded rapidly over the past 10 years, and there is now an even greater need to understand the biological mechanisms of resistance and to develop noninvasive biomarkers to guide treatment. The androgen receptor (AR) is known to be involved in the pathogenesis and progression of prostate cancer. Recently, highly sensitive next-generation sequencing and PCR-based methods for analyzing androgen receptor gene (AR) copy numbers (CN) and mutations in plasma were established in cell-free DNA (cfDNA) of patients with castration-resistant prostate cancer (CRPC) treated with different drugs. The study of cfDNA holds great promise for improving treatment in CRPC, especially in the advanced stage of the disease. Recent findings showed the significant association of plasma AR aberrations with clinical outcome in CRPC patients treated with AR-directed therapies, whereas no association was observed in patients treated with taxanes. This suggests the potential for using plasma AR as a biomarker for selecting treatment, i.e., hormone therapy or chemotherapy, and the possibility of modulating taxane dose. In recent years, plasma AR status has also been investigated in association with novel agents, such as 177Lu-PSMA radioligand therapy and PARP inhibitors. This review will focus on AR testing in plasma that may have clinical utility for treatment selection in advanced prostate cancer.
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Neron, Mathias, Arnaud Guille, Lucie Allegre, Pierre-Emmanuel Colombo, Cristina Leaha, José Adelaide, Nadine Carbuccia, et al. "Investigation of Molecular Features Involved in Clinical Responses and Survival in Advanced Endometrial Carcinoma Treated by Hormone Therapy." Journal of Personalized Medicine 12, no. 5 (April 19, 2022): 655. http://dx.doi.org/10.3390/jpm12050655.
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Hormone therapy (HT) is an effective treatment for metastatic endometrial carcinoma (mEC), with limited toxicity and low cost. We focused on molecular analysis of mECs treated by HT and, for the first time to date, we compared the genomic profiles of paired metastasis and primary ECs. The main objective was to identify predictive factors of the response to HT as well as specific altered signaling pathways driving mEC biology. From 1052 patients with EC treated by HT in two French cancer centers, 32 with endometrioid EC and 6 with high grade serous EC were included. We evaluated hormone receptors (HR) and mismatch repair proteins expression by immunohistochemistry and gene alterations by targeted next-generation sequencing and array-based comparative genomic hybridization. Several variables were tested in univariate and multivariate analyses to identify potential associations with (i) the clinical benefit of HT (CBHT) and (ii) a longer response (>18 months) (LRHT) and overall survival (OS). We compared the biological and genomic profiles of 11 primary/metastatic EC pairs. Thirty tumors (78.9%) were HR-positive and 6 (15.8%) showed microsatellite instability (MSI). The genomic profiles of 34 tumors showed an average altered genome of 3.26%, DNA repair homologous recombination deficiency in five tumors (14.7%), and 17 regions significantly targeted by amplification/deletion. Thirty-three tumors had 273 variants (158 genes, median of 7 mutations/sample), including 112 driver mutations. TP53, PTEN, PPP2R1A, ARID1A, FGFR2, and PIK3CA were the most frequently mutated. Based on the genomic status, nine oncogenic pathways were altered in more than 25% of primary EC. Clinically, 22 (57.9%) and 6 (15.8%) patients presented CBHT and LRHT, respectively. Neither oncogenic pathways alterations nor the variables tested were associated with CBHT and LRHT. Only patient’s age, mitotic index and the presence of at least one HR were associated with OS. Paired analysis of the primary/metastatic samples showed that among the 22 mutations acquired in the metastatic counterparts, the most frequently targeted genes were involved in pathways that might confer a selective advantage to cancer metastasis including hormone resistance. In conclusion, only patient’s age, mitotic index and the presence of at least one HR were associated with OS. The identification of gene mutations newly acquired in metastasis might help to better understand the formation of EC metastasis and select the best actionable candidates for HT-treated patients at the metastatic stage.
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Tolaney, S. "Abstract TF2-2: Heterogeneity in treatment outcomes for HER2+ breast cancer - Clinical management strategies." Cancer Research 82, no. 4_Supplement (February 15, 2022): TF2–2—TF2–2. http://dx.doi.org/10.1158/1538-7445.sabcs21-tf2-2.
Full textAbstract:
Abstract HER2-positive breast cancers are complex tumors that are clinically and biologically heterogeneous. Even within HER2+ breast cancer, there are different molecular subtypes, mutational profiles, levels of HER2 protein, and immune infiltration. Additionally, HER2 may not be expressed homogeneously among all the cancer cells in the same tumor, some tumors may have low HER2 expression, while other tumors evolve during treatment. These molecular differences help explain why patients do not benefit to the same extent to HER2-directed therapies. We will review data regarding outcomes for tumors with known tumor heterogeneity, hormone receptor positivity, HER2-low positivity, and cases where brain metastases may be present. We will discuss optimal clinical management in the modern era with multiple HER2-directed therapies, including next-generation antibody-drug conjugates. Future strategies to tailor therapy to the individual patient will need to not just factor in anatomic tumor burden, but also key molecular features. Citation Format: S Tolaney. Heterogeneity in treatment outcomes for HER2+ breast cancer - Clinical management strategies [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr TF2-2.