Search

Background: Until recently, treatment options for patients with hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) and resistance to endocrine therapy were limited to chemotherapy. This real-world study describes treatment patterns and outcomes in patients treated with chemotherapy in the United States before approval of antibody-drug conjugates., Patients and Methods: This retrospective, observational study included adults with HR+/HER2- mBC from the ConcertAI Patient360™ Breast Cancer dataset who initiated their first chemotherapy in the metastatic setting between January 2011 and June 2021. Treatment patterns were described; real-world overall survival, time to next treatment or death, and real-world progression-free survival were evaluated for all eligible patients and patients treated with subsequent chemotherapy. Index dates were the start date of each chemotherapy treatment., Results: Among 1545 eligible patients, 76% were white, 12% had Eastern Cooperative Oncology Group performance status ≥2, 38% had de novo mBC, and median age was 61 years (range, 52-69 years). Within the index period, capecitabine was used the most as the first chemotherapy agent and decreased in later treatments, while the use of eribulin increased between first and fourth chemotherapies. Median (95% confidence interval) real-world overall survival was 23.3 months (21.3-25.4 months) from start of first chemotherapy, time to next treatment or death was 6.5 months (5.9-7.1 months), and real-world progression-free survival was 6.9 months (6.4-7.6 months); median times from second, third, and fourth chemotherapies decreased with each additional chemotherapy treatment., Conclusions: This real-world study demonstrates that for patients with HR+/HER2- mBC, chemotherapy provides relatively limited survival benefit which decreases with each additional chemotherapy line, and highlights the need for improved treatment options., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Capivasertib is a potent, selective pan-AKT inhibitor. In CAPItello-291, the addition of capivasertib to fulvestrant resulted in a statistically significant (P < 0.001) improvement in progression-free survival over fulvestrant monotherapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer and disease progression on or after aromatase inhibitor-based therapy. Characterization of the capivasertib-fulvestrant adverse event (AE) profile as managed in CAPItello-291 can inform future management guidance and optimize clinical benefit., Patients and Methods: Seven hundred and eight patients were randomized 1 : 1 to capivasertib (400 mg twice daily; 4 days on, 3 days off) or placebo, plus fulvestrant, on a 4-week cycle. Dose reductions/interruptions for capivasertib/placebo were permitted (up to two dose reductions). Safety analyses included exposure, AE, and clinical laboratory data and were conducted in patients who received at least one dose of capivasertib, fulvestrant, or placebo. Frequent AEs associated with phosphoinositide 3-kinase (PI3K)/protein kinase (AKT) pathway inhibition (diarrhea, rash, hyperglycemia) were characterized using group terms. AEs were summarized using descriptive statistics; time-to-event analyses were conducted., Results: Safety analyses included 705 patients: capivasertib-fulvestrant (n = 355) and placebo-fulvestrant (n = 350). Frequent any-grade AEs with capivasertib-fulvestrant were diarrhea (72.4%), rash (38.0%), and nausea (34.6%); frequent grade ≥3 AEs were rash (12.1%), diarrhea (9.3%), and hyperglycemia (2.3%). Diarrhea, rash, and hyperglycemia occurred shortly after starting capivasertib-fulvestrant [median days to onset (interquartile range) of any grade: 8 (2-22), 12 (10-15), and 15 (1-51), respectively], and were managed with supportive medications, dose reductions, interruptions, and/or discontinuation. Discontinuation rates were 2.0%, 4.5%, and 0.3%, respectively. Overall, 13.0% discontinued capivasertib due to AEs., Conclusions: Frequent AEs associated with PI3K/AKT pathway inhibition occurred early and were manageable. The low rate of treatment discontinuations suggests that, when appropriately managed, these AEs do not pose a challenge to clinical benefit., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In the past decade, significant progress was made in treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC), but many clinical questions remain. Cyclin-dependent kinase 4/6 inhibitors are now widely used in combination with endocrine therapy (ET) as standard of care, having demonstrated significant progression-free survival versus ET, and also significant overall survival benefits in the metastatic setting. Inhibition of the PI3K/AKT/mTOR intracellular signaling pathway coupled with ET typically follows first-line therapies. Novel endocrine options including oral selective estrogen receptor down-regulators (SERDs) are in late phases of development, with elacestrant being the first oral SERD to be approved for ESR1-mutant mBC. However, endocrine-refractory disease is inevitable in most patients and represents an area of unmet need, with current recommended options offering poor efficacy, undesirable toxicity, and reduced quality of life. Breakthrough advances in the metastatic setting came via the development of antibody-drug conjugates, which have the advantage of delivering cytotoxic payloads to tumor cells with higher tumor selectivity. Trastuzumab deruxtecan offers a novel therapeutic option for patients with HR+/HER2-low mBC and sacituzumab govitecan is a novel therapeutic option for patients with HR+/HER2- mBC, including those with unmet treatment need in the later-line endocrine-refractory setting. Data gaps still exist regarding optimal sequencing of these novel agents; additional studies into mechanisms of resistance in the metastatic setting would provide further insights. Herein, we describe the current treatment options for HR+/HER2- mBC, including the latest practice-impacting data, and provide commentary on future directions., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Jhaveri has received consulting/advisory board fees from Novartis, Pfizer, Bristol Myers Squibb, Jounce Therapeutics, Taiho Oncology, Genentech/Roche, AbbVie, Eisai, AstraZeneca, Blueprint Medicine, Daiichi Sankyo, Seattle Genetics, Lilly/Loxo Oncology, Stemline/Menarini, Sun Pharma Advanced Research Company Ltd, Scorpion Therapeutics; and has received research funding from Novartis, Genentech, AstraZeneca, ADC Therapeutics, Novita Pharmaceuticals, Debiopharm, Pfizer, Lilly Pharmaceuticals, Zymeworks, Gilead, PUMA Biotechnology, Scorpion Therapeutics and Merck Pharmaceuticals. Dr. Marmé reports personal fees from Roche, AstraZeneca, Pfizer, Tesaro, Novartis, Amgen, PharmaMar, Genomic Health, CureVac, EISAI, Clovis, Gilead/Immunomedics, GSK, MSD, Seagen, Myriad, Pierre-Fabre, Daiichi- Sankyo, outside the submitted work., (Copyright © 2023. Published by Elsevier Ltd.)

Triple negative breast cancer (TNBC) remains the subtype with poorest prognosis. Despite the subtype's heterogeneity, there is still a paucity in effective targeted therapeutics that offer both good efficacy and tolerability, and chemotherapy remains the backbone of modern TNBC therapy. In the past few years, immunotherapy as well as novel therapeutic modalities like antibody-drug conjugates (ADCs) have shown clinical benefit and have been FDA approved in various clinical stages of unselected TNBC. However, there has not been similar advancement in molecularly targeted therapies, especially when compared to advancements seen in hormone receptor (HR)-positive or HER2-positive breast cancer. PARP inhibitors have been approved for BRCA-mutated TNBC, but responses are short-lived, and resistance remains a barrier for current treatment. PI3K pathway inhibitors approved in HR+ breast cancer has not worked for TNBC and continue to have significant dose-limiting adverse effects. EGFR inhibition has been thoroughly explored in TNBC, but all trials so far have shown minimal efficacy. Nevertheless, despite these setbacks, current research in targeted therapy for TNBC holds great promise in overcoming the barriers of the past and developing novel therapeutic approaches for the future. In this review, we describe molecular targets both identified and validated in the treatment of TNBC, discuss the historical efforts towards development of targeted agents and current areas of improvement, and address promising advances that have the potential to improve outcomes in this heterogenous and aggressive breast cancer subtype. Immunotherapy, ADCs, and AR targeting will be discussed in separate reviews of this edition., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T., Patients and Methods: Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing., Results: ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response., Conclusions: The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy., Competing Interests: Disclosure KJ: Consultant/Advisory Board: Novartis, AstraZeneca, Pfizer, BMS, Jounce Therapeutics, Taiho Oncology, Genentech/Roche, Lilly Pharmaceuticals/Loxo Oncology, AbbVie, Eisai, Blueprint Medicines, Seattle Genetics, Daiichi Sankyo, Gilead, Olema Pharmaceuticals, Sun Pharma Advanced Research Company Ltd., Menarini/Stemline, and Scorpion Therapeutics. Research Funding: Novartis, Genentech/Roche, AstraZeneca, Debio Pharmaceuticals, Pfizer, Lilly Pharmaceuticals/Loxo Oncology, Zymeworks, Gilead, Puma Biotechnology, Merck Pharmaceuticals, and Scorpion Therapeutics. HW: His institution received financial compensation on his behalf for advisory boards, lecture fees and/or consultancy fees from Daiichi Sankyo, Gilead, Lilly, Augustine Therapeutics, AstraZeneca, Immutep Pty, MSD, and Roche. He received travel support from Gilead, Daiichi Sankyo, and Pfizer. SAH: Contracted research paid to institution +/- editorial support for authorship: Ambrx, Arvinas, AstraZeneca, Bayer, Celcuity, Cytomx, Daiichi Sankyo, Dantari, Dignitana, Genentech/Roche, G1-Therapeutics, Gilead, Greenwich Life Sciences Inc., GSK, Immunomedics, Eli Lilly, Loxo, Macrogenics, Novartis, OBI Pharma, Orinove, Orum, Pfizer, Phoenix Molecular Designs, Ltd., Pieris, PUMA, Radius, Sanofi, Seattle Genetics/Seagen, and Zymeworks. Speaking: Daiichi Sankyo (2021). AG-Z: Advisory/Consultancy: AstraZeneca, Novartis, MSD, Pierre-Fabre, and Exact Science. Speaker Bureau/Expert testimony: Roche, AstraZeneca, Novartis, MSD, Pfizer, Lilly, and Pierre-Fabre. Research grant/Funding (institution): Pfizer. Travel/Accommodation/Expenses: Roche, Novartis, and Pfizer. NU: Consultant/Advisory Board: Novartis, Eli Lilly, BioTheranostics, Gilead. AB: Consultant: AstraZeneca, Pfizer, Novartis, Lilly, Genentech/Roche, Seagen, Daiichi Sankyo, Merck, Agendia, Sanofi, Puma, Myriad, and Gilead; research support: Agendia and AstraZeneca. HP: Research grants to institution: Adlai Nortye USA, Ambrx, Aprea Therapeutics AB, Array BioPharma, AstraZeneca, BJ Bioscience, Bristol-Myers Squibb, Daiichi Pharmaceutical, Elicio Therapeutics, Exelixis, Fate Therapeutics, Genentech, GlaxoSmithKline, Gossamer Bio, Hutchison MediPharma, ImmuneOncia Therapeutics, ImmunoGen, Mabspace Biosciences, MacroGenics, Merck, Mirati Therapeutics, Novartis Pharmaceuticals, Oncologie, PsiOxus Therapeutics, RePare Therapeutics, Seattle Genetics, Synermore Biologics, TopAlliance Biosciences, Turning Point Therapeutics, Vedanta Biosciences, Xencor. ESY: Research funding: Puma Biotechnology; Advisory boards: Bayer, Clovis; Consultant: AstraZeneca. IS: Institutional Research Funding: Roche/Genentech, Puma Biotechnology, MSD, Merck, AstraZeneca, Incyte, Orion, Genmab, Bristol-Myers Squibb, Bayer/Loxo Oncology, Lilly Pharmaceuticals/Loxo Oncology, Novartis, Pfizer, Amgen, Repare Therapeutics. Honoraria: AstraZeneca. Support for travel and meeting attendance: Roche, Novartis, Merck/Pfizer, Incyte, and AstraZeneca. SR: Consultant/Advisory board: Novartis, AstraZeneca, Gilead, and Daiichi Sankyo. MBh: Consulting/Advisory Board: Daiichi Sankyo, Merck, Pfizer, and AstraZeneca. SV: Funding from Pfizer directly to institution for conducting clinical trial. MA: Consulting or advisory role: Pfizer, AstraZeneca, Menarini, Novartis, Daiichi Sankyo, and Gilead. Speaker’s bureau: Pfizer, Novartis, and Gilead. Research funding: AstraZeneca. F-CB: Consulting or advisory role: Pfizer; AstraZeneca; Lilly; Novartis; Menarini; Sanofi; GSK; Rain Oncology; Caris Life Sciences; GE Healthcare; Exact Sciences; Gilead. Speaker's bureau: Pfizer; Novartis; AstraZeneca; Roche; Lilly; Rain Oncology; Daiichi Sankyo; and Menarini-Stemline. Research Funding: Novartis; Pfizer; Menarini Silicon Biosystems; Prolynx; Merck KGaA; and GE Healthcare. SL: Receives research funding to her institution from Novartis, Bristol Myers Squibb, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, and Seattle Genetics. She has acted as consultant (not compensated) to Seattle Genetics, Novartis, Bristol Myers Squibb, Merck, AstraZeneca, Eli Lilly, Pfizer, Gilead Therapeutics, and Roche-Genentech. She has acted as consultant (paid to her institution) to Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, Puma Biotechnology, Inc., Pfizer, Gilead Therapeutics, Seattle Genetics, Daiichi Sankyo, Merck, Amunix, Tallac Therapeutics, Eli Lilly, and Bristol Myers Squibb. JC: Has taken part in advisory boards for Puma Biotechnology. His unit is the recipient of a peer-reviewed grant from Science Foundation Ireland (an Irish government organization) which is part-funded by Puma Biotechnology Inc. Neither he nor his spouse own Puma Biotechnology stock. MEB: Medical advisory board of Strata Oncology; Research funding from AbbVie, Arcus, Apollomics, Elevation Oncology, Endeavor, Genetech, Puma, Loxo Oncology, and Seagen. SAP-P: Clinical trial research support/grant funding through the institution from AbbVie, Inc., ABM Therapeutics, Inc., Acepodia, Inc., Alkermes, Aminex Therapeutics, Amphivena Therapeutics, Inc., BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol-Myers Squibb, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Curis, Inc., Cyclacel Pharmaceuticals, Daiichi Sankyo, Eli Lilly, ENB Therapeutics, Epigenetix Inc., Five Prime Therapeutics, F-Star Beta Limited, F-Star Therapeutics, Gene Quantum, Genmab A/S, Gilead Sciences, Inc., GlaxoSmithKline, Helix BioPharma Corp., Hengrui Pharmaceuticals, Co., Ltd., HiberCell, Inc., Immorna Biotherapeutics, Inc., Immunomedics, Inc., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., Jiangsu Simcere Pharmaceutical Co., Ltd., Lytix Biopharma AS, Medimmune, LLC., Medivation, Inc., Merck Sharp and Dohme Corp., Nectin Therapeutics, Ltd., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Phanes Therapeutics, Principia Biopharma, Inc., Puma Biotechnology, Inc., Purinomia Biotech, Inc., Rapt Therapeutics, Inc., Replimune, Seattle Genetics, Silverback Therapeutics, Synlogic Therapeutics, Taiho Oncology, Tesaro, Inc., TransThera Bio, ZielBio, Inc., NCI/NIH, P30CA016672—Core Grant (CCSG Shared Resources); and consulting fees from CRC Oncology. JMS: Research grant support: AstraZeneca and Strata Oncology. SC: Advisory/Consultancy: Novartis, F. Hoffmann-La Roche, Pfizer, Eli Lilly, AstraZeneca, Amgen, Gilead, Merck, and Exact Sciences. Research funding to the institution: Novartis, F. Hoffmann-La Roche, Pfizer, Genomic Health/Exact Sciences, AstraZeneca, Genentech, Celgene, Amgen, BMS, Merck, Sanofi, Puma, and Gilead. CS: Consulting, advisory role or travel grants from: AstraZeneca, AX'Consulting, Byondis B.V, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann-La Roche Ltd., Lilly, MediTech, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Pierre-Fabre, PintPharma, Puma Biotechnology, Seagen, and Zymeworks. JAG-S: Consulting or advisory role: Novartis Pharmaceuticals Corporation, AstraZeneca, Lilly, Seagen, Daiichi Sankyo, Gilead Sciences, Exact Sciences, and Stemline Menarini; speakers bureau: Novartis Pharmaceuticals Corporation, Lilly, AstraZeneca, and Stemline Menarini; travel, accommodations, expenses: Daiichi Sankyo, Gilead Sciences, and Exact Sciences. VG: Advisory Board: Boehringer. Research Funding: Bayer, Boehringer, Roche. Institutional Funding: Genentech, Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astellas, Fibrogen, Amcure, Natera, Sierra Oncology, AstraZeneca, Medimmune, BMS, and MSD. ENG-Y: Honoraria from Novartis, Pfizer, Eli Lilly, MSD, and AstraZeneca. CM: Has received research grants from Puma Biotechnology and Pfizer. She received consulting fees from AstraZeneca, Olaris, Novartis, and Sanofi. ABH: Reports stock and other ownership interests in Pfizer (immediate family member) and research funding from Takeda. JWG: has received institutional research funding from Puma Biotechnology Inc. RB: Receives research grant from Puma; has performed consulting for Genentech. JSKB: Employee (and stockholder) of Tempus Labs. LDE, DD, AF, and AW: Employees and stockholders of Puma Biotechnology. CLA: Has received research grants from Pfizer, Lilly, and Takeda. He serves or has served as scientific advisor to Novartis, Lilly, AstraZeneca, Daiichi Sankyo, Merck, Immunomedics, OrigiMed, Sanofi, TAIHO Oncology, and Puma Biotechnology. DBS: Has served as a consultant for/received honorarium from Pfizer, Vividion Therapeutics, Scorpion Therapeutics, FORE Therapeutics, Fog Pharma, Elsie Biotechnologies, Fog Pharma, Rain Oncology, Function Oncology, and BridgeBio. All other authors have declared no conflicts of interest. Data Sharing The authors declare that the data supporting the findings of this study are available within the article. Qualified researchers and study participants may submit requests for other study documentation and clinical trial data to clinicaltrials@pumabiotechnology.com for consideration., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Endocrine therapy (ET) is the cornerstone of management in hormone receptor (HR)+ breast cancer (BC). Indeed, targeting the estrogen receptor (ER) signaling at different levels is a successful strategy, since BC largely relies on the ER signaling as a driver of tumorigenesis and progression. In metastatic BC, progression of disease typically occurs due to either ligand-independent ER signaling, which favors tumor proliferation and survival in the absence of hormonal stimuli, or an ER-independent signaling, which exploits alternative transcription pathways. For instance, estrogen receptor 1 (ESR1) mutations induce constitutive ER activity, in turn upregulating ER-dependent gene transcription and causing resistance to estrogen depleting therapies. The largest unmet need lies after progression on ET + cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, where fulvestrant alone provides an average 2-3-month PFS. In this context, novel oral selective estrogen receptor degraders (SERDs) and other next-generation ETs are being investigated, both as single agents and in combination with targeted therapies. Elacestrant, the next generation ET in most advanced clinical development and the first to be FDA approved, demonstrated improved outcomes compared to standard ETs in ET pre-treated HR+/HER2- metastatic BC in the phase 3 EMERALD clinical trial. Additionally, other agents are showing promising results in both preclinical and early phase clinical settings. In this review, emerging data related to oral SERDs and other novel ETs in managing HR+/HER2- BC are presented. Major challenges and future perspectives related to the optimal sequence of therapeutic options and the molecular landscape of endocrine resistance are also provided., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CCo, has no potential conflicts of interest to disclose. CDA is a consultant and/or advisory board member for AstraZeneca, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer and Roche. All the competing interests were outside the submitted work. GB is a consultant and/or advisory board member for Amgen, AstraZeneca, Chugai, Daiichi Sankyo, EISAI, Eli Lilly, Genomic Health, Merck Sharp & Dohme, Neopharm, Novartis, Pfizer, Roche and Sanofi. All the competing interests were outside the submitted work. LM reports speaker/consultant honoraria by Novartis, Pfizer, Lilly. Research Grant from Novartis and Pfizer. All the competing interests were outside the submitted work. MG reports honoraria from Roche, Pfizer, AstraZeneca, Novartis, Celgene, Eli Lilly, Amgen, and Eisai. All the competing interests were outside the submitted work. EH reports institutional research funding from OncoMed, Genentech/Roche, Zymeworks, Rgenix, ArQule, Clovis, Silverback Therapeutics, Millenium, Acerta Pharma, Sermonix Pharmaceuticals, Torque, Black Diamond, Karyopharm, Infnity Pharmaceuticals, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Fochon, Molecular Templates, Onconova Therapeutics, Hutchinson MediPharma, MedImmune, SeaGen, Puma Biotechnology, Compugen, TapImmune, Lilly, Pfzer, H3 Biomedicine, Takeda, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, Merck, PharmaMar, Olema, Polyphor, Immunogen, Plexxicon, Amgen, Akesobio Australia, and Shattuck Labs; consultancy/advisory roles with Genentech/Roche, Boehringer Ingelheim, Novartis, Dantari, Eli Lilly, Merck, Puma, Silverback Therapeutics, CytomX, Pfzer, Mersana, Black Diamond, H3 Biomedicine, Daiichi Sankyo, AstraZeneca, Arvinas, Deciphera Pharmaceuticals, Eisai, and Seattle Genetics. All the competing interests were outside the submitted work. RJ receives research funding from Pfizer and Lilly and is a consultant for Carrick Therapeutics and Luminex. All the competing interests were outside the submitted work. KJ reports fees for consulting or advisory role for Novartis, Pfizer, AstraZeneca, Jounce Therapeutics, Synthon, Intellisphere, Bristol Myers Squibb, Genentech, AbbVie, Lilly, BluePrint Medicines, Seattle Genetics, Daiichi Sankyo, Biotheranostics, SunPharma Pvt Ltd, Taiho Oncology, Sanofi. Research Funding from Novartis (Inst), Genentech (Inst), Debiopharm Group (Inst), ADC Therapeutics (Inst), Pfizer (Inst), Novita Pharmaceuticals (Inst), Clovis Oncology (Inst), Lilly (Inst), Zymeworks (Inst), Immunomedics (Inst), Puma Biotechnology (Inst), VelosBio/Merck (Inst), AstraZeneca (Inst), Travel, Accommodations, travel expenses from Taiho Pharmaceutical, Jounce Therapeutics, Pfizer, AstraZeneca, Intellisphere. All the competing interests were outside the submitted work. GC reports personal fees for consulting, advisory role and speakers’ bureau from Roche/Genentech, Novartis, Pfizer, Lilly, Foundation Medicine, Samsung and Daiichi Sankyo; honoraria from Ellipses Pharma and fees for travel and accommodations from Roche/Genentech and Pfizer. All the competing interests were outside the submitted work. CCr reports personal fees for consulting, advisory role and speakers’ bureau from Lilly, Roche, Novartis, MSD, Seagen, Gilead and Pfizer. All the competing interests were outside the submitted work., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The estrogen receptor (ER) is an important driver in the proliferation, tumorigenesis, and progression of breast cancers, and targeting ER signaling at different levels is a successful strategy in the control of hormone receptor positive (HR+) breast cancer. Endocrine therapy has been the treatment of choice for HR+ breast cancer in the early and advanced stages with multiple agents, including selective estrogen receptor modulators (SERMS), selective estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs), which vary in their mechanisms of action and pharmacokinetics. Combination strategies also employ cyclin dependent kinase 4 and 6 and phosphatidylinositol 3-kinase to maximize the benefits of endocrine therapy. This paper reviews the clinical development of SERDs and other novel ER inhibitors, as well as combination strategies to overcome mechanisms of ER pathway escape. It also assesses the advantages of newer oral ER inhibitors with increased bioavailability, improved therapeutic index, better administration, and increased efficacy, as well as discussing future directions in the field., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The tropomyosin receptor kinase (TRK) pathway controls appetite, balance, and pain sensitivity. While these functions are reflected in the on-target adverse events (AEs) observed with TRK inhibition, these AEs remain under-recognized, and pain upon drug withdrawal has not previously been reported. As TRK inhibitors are approved by multiple regulatory agencies for TRK or ROS1 fusion-positive cancers, characterizing these AEs and corresponding management strategies is crucial., Patients and Methods: Patients with advanced or unresectable solid tumors treated with a TRK inhibitor were retrospectively identified in a search of clinical databases. Among these patients, the frequency, severity, duration, and management outcomes of AEs including weight gain, dizziness or ataxia, and withdrawal pain were characterized., Results: Ninety-six patients with 15 unique cancer histologies treated with a TRK inhibitor were identified. Weight gain was observed in 53% [95% confidence interval (CI), 43%-62%] of patients and increased with time on TRK inhibition. Pharmacologic intervention, most commonly with glucagon-like peptide 1 analogs or metformin, appeared to result in stabilization or loss of weight. Dizziness, with or without ataxia, was observed in 41% (95% CI, 31%-51%) of patients with a median time to onset of 2 weeks (range, 3 days to 16 months). TRK inhibitor dose reduction was the most effective intervention for dizziness. Pain upon temporary or permanent TRK inhibitor discontinuation was observed in 35% (95% CI, 24%-46%) of patients; this was more common with longer TRK inhibitor use. TRK inhibitor reinitiation was the most effective intervention for withdrawal pain., Conclusions: TRK inhibition-related AEs including weight gain, dizziness, and withdrawal pain occur in a substantial proportion of patients receiving TRK inhibitors. This safety profile is unique relative to other anticancer therapies and warrants careful monitoring. These on-target toxicities are manageable with pharmacologic intervention and dose modification., Competing Interests: Disclosure JF has received honoraria from Genentech. AL has received research funding from Bristol Myers Squibb and NantOmics and holds equity in Sanofi. MO has served on advisory boards for PharmaMar, Novartis, and Targeted Oncology, and received travel expenses from Bristol Myers Squibb and Merck. YRM-G has received travel expenses from AstraZeneca. BTL holds two institutional patents (US62/685,057, US62/514,661), and has served on advisory boards for Genentech (subsidiary of Roche), Eli Lilly, Guardant Health, Hengrui Therapeutics, Mersana Therapeutics, and Thermo Fisher Scientific, received travel expenses from MORE Health and Resolution Bioscience, and received research funding from Amgen, AstraZeneca, BioMedValley Discoveries, Daiichi Sankyo, Genentech, GRAIL, Guardant Health, Eli Lilly, Hengrui Therapeutics, Illumina, and MORE Health. JJH has received consulting fees from Bristol Myers Squibb, Cytomx, Eli Lilly, Eisai, Exelixis, Imvax, QED, and research funding from Bristol Myers Squibb. GI has received research funding from Janssen, Mirati Therapeutics, and Novartis, and consulting fees from Mirati Therapeutics. MMG has received honoraria from Bayer and Flatiron Health, served on advisory boards for Bayer, Boehringer Ingelheim, Epizyme, Daiichi Sankyo, Karyopharm, and Springworks Therapeutics, served on a speakers’ bureau for Amgen, and received travel expenses from Epizyme. AS has received research funding from Eli Lilly, Kura Oncology, Merus, Northern Biologics, and Surface Oncology. DMH owns stock in Fount Therapeutics, has served on advisory boards for ArQule, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai Pharma, CytomX, Debiopharm, Fount Therapeutics, Genentech, Eli Lilly, Janssen, Jazz Pharma, Pfizer, and Puma Biotechnology, received research funding from AstraZeneca, Bayer, Loxo Oncology, and Puma Biotechnology, and received travel expenses from Chugai Pharma and Genentech; he is currently employed by and holds equity in Loxo Oncology, a subsidiary of Eli Lilly. AD has received honoraria and/or served on advisory boards for 14ner/Elevation Oncology, Abbvie, ArcherDX, AstraZeneca, Axis Pharma, Bayer, Beigene, BergenBio, Blueprint Medicines, Exelixis, Helsinn, Hengrui Therapeutics, Loxo Oncology (subsidiary of Eli Lilly), Monopteros, MORE Health, Remedica, Roche (subsidiaries Genentech and Ignyta), Pfizer, Takeda (subsidiaries Ariad and Millennium), TP Therapeutics, Tyra Biosciences, and Verastem; and received research funding from Exelixis, Foundation Medicine GlaxoSmithKline, Pfizer, PharmaMar, Teva, and Taiho. All research funding was provided to the institution. All other authors report no financial relationships., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) is a national precision medicine study incorporating centralized genomic testing to direct refractory cancer patients to molecularly targeted treatment subprotocols. This treatment subprotocol was designed to screen for potential signals of efficacy of ado-trastuzumab emtansine (T-DM1) in HER2-amplified histologies other than breast and gastroesophageal tumors., Methods: Eligible patients had HER2 amplification at a copy number (CN) >7 based on targeted next-generation sequencing (NGS) with a custom Oncomine AmpliSeq™ (ThermoFisher Scientific) panel. Patients with prior trastuzumab, pertuzumab or T-DM1 treatment were excluded. Patients received T-DM1 at 3.6 mg/kg i.v. every 3 weeks until toxicity or disease progression. Tumor assessments occurred every three cycles. The primary end point was centrally assessed objective response rate (ORR). Exploratory end points included correlating response with HER2 CN by NGS. The impact of co-occurring genomic alterations and PTEN loss by immunohistochemistry were also assessed., Results: Thirty-eight patients were enrolled and 36 included in efficacy analysis. Median prior therapies in the metastatic setting was 3 (range 0-9; unknown in one patient). Median HER2 CN was 17 (range 7-139). Partial responses were observed in two (5.6%) patients: one mucoepidermoid carcinoma of parotid gland and one parotid gland squamous cell cancer. Seventeen patients (47%) had stable disease including 8/10 (80%) with ovarian and uterine carcinomas, with median duration of 4.6 months. The 6-month progression-free survival rate was 23.6% [90% confidence interval 14.2% to 39.2%]. Common toxicities included fatigue, anemia, fever and thrombocytopenia with no new safety signals. There was a trend for tumor shrinkage with higher levels of gene CN as determined by the NGS assay., Conclusion: T-DM1 was well tolerated. While this subprotocol did not meet the primary end point for ORR in this heavily pre-treated diverse patient population, clinical activity was seen in salivary gland tumors warranting further study in this tumor type in dedicated trials., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: To evaluate the feasibility of semi-LASER renal magnetic resonance spectroscopy (MRS) in healthy volunteers and establish signature chemical composition of normal renal tissue towards future application for renal carcinoma characterization and grading., Materials and Methods: 14 healthy volunteers were recruited after informed consent. Single voxel 1 H spectra were acquired on a 3T MRI system using a semi-LASER sequence, employing outer-volume suppression and VAPOR water suppression with multiple averages in multiple breath-holds. Off-line processing and automatic correction for zero-order phase and frequency using the water resonance or residual water resonance for water-suppressed acquisitions was performed., Results: 11 volunteers successfully completed the entire examination. Phase and frequency correction was necessary to obtain optimal data quality prior to signal summation in few datasets. No lipid resonance was observed in any spectra from the unsuppressed water acquisitions, either in individual transients or in corrected summed spectra opposed to previously reported studies. No signal from other metabolites, such as choline-containing compounds, was observed in any dataset., Conclusion: Semi-LASER renal MRS is technically feasible. Normal renal parenchyma does not demonstrate detectable levels of lipid or choline. This may provide a reference point for future application of this technique for noninvasive renal carcinoma histologic subtype characterization and grade., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Heat shock protein (HSP) 90, a viable target for cancer treatment, mediates the maturation and stabilization of client oncoproteins. HSP90 inhibitors (HSP90i) are potentially active in a variety of tumors, but therapeutic benefit is confirmed in only a small subset. We explored potential biomarkers across multiple studies of HSP90i in advanced solid tumors., Patients and Methods: Archived tumor specimens from patients treated with HSP90i in 7 different phase I/II trials at Memorial Sloan Kettering Cancer Center were identified. Tumor tissue was tested using immunohistochemistry; estrogen, progesterone, and androgen receptors ≥ 1% positive and < 1% negative; HSP90 and HSP70: 0, 1 + negative, and 2+, 3 + positive; phosphatase and tensin homolog: 0 negative, 1 reduced, and 2 positive; HER2: 0, 1 + negative, 2 + equivocal, 3 + positive; and epidermal growth factor receptor: 0 negative, and 1+, 2+, 3 + positive. The expression of the biomarker panel was correlated with clinical benefit (CB) (defined by overall response [ORR] or CB by the "8-week" scan) using Fisher exact test., Results: Adequate tissue was available for 51 of 158 patients (32%), including 10 different solid tumors. Of these, 71% (36 of 51) and 51% (26 of 51) patients met the criteria to assess CB by best ORR or by the "8-week scan" assessment, respectively. Breast was the most frequent tumor. The mean duration of HSP90i therapy was 55 days (range, 16-411 days). There were 16 responses (4 partial response; 12 stable disease); 13 of 16 responses strongly correlated with HER2-positive status (P = .001)., Conclusion: Our findings suggest HER2 as a sensitive client and perhaps the only effective biomarker for sensitivity to these HSP90i., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Inflammatory breast cancer (IBC) is an aggressive and rare cancer with a poor prognosis and a need for novel targeted therapeutic strategies. Preclinical IBC data showed strong activation of the phosphatidylinositide-3-kinase/mammalian target of rapamycin (mTOR) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, and expression of inflammatory cytokines and tumor-associated macrophages (TAMs)., Patients and Methods: Archival tumor tissue from 3 disease types (IBC treated with neoadjuvant chemotherapy [NAC], n = 45; invasive ductal carcinoma [IDC] treated with NAC [n = 24; 'treated IDC'; and untreated IDC [n = 27; 'untreated IDC']) was analyzed for the expression of biomarkers phospho-S6 (pS6) (mTOR), phospho-JAK2 (pJAK2), pSTAT3, interleukin (IL)-6, CD68 (monocytes, macrophages), and CD163 (TAMs). Surrounding nontumor tissue was also analyzed., Results: Biomarker levels and surrogate activity according to site-specific phosphorylation were shown in the tumor tissue of all 3 disease types but were greatest in IBC and treated IDC and least in untreated IDC for pS6, pJAK2, pSTAT3, and IL-6. Of 37 IBC patients with complete biomarker data available, 100% were pS6-positive and 95% were pJAK2-positive. In nontumor tissue, biomarker levels were observed in all groups but were generally greatest in untreated IDC and least in IBC, except for JAK2., Conclusion: IBC and treated IDC display similar levels of mTOR and JAK2 biomarker activation, which suggests a potential mechanism of resistance after NAC. Biomarker levels in surrounding nontumor tissue suggested that the stroma might be activated by chemotherapy and resembles the oncogenic tumor-promoting environment. Activation of pS6 and pJAK2 in IBC might support dual targeting of the mTOR and JAK/STAT pathways, and the need for prospective studies to investigate combined targeted therapies in IBC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Ganetespib is a small molecule, nongeldanamycin HSP90 inhibitor with potent inhibitory effects on HSP90-dependent oncoproteins of relevance to breast cancer pathogenesis. We therefore tested ganetespib in an unselected cohort of patients with MBC., Patients and Methods: Patients were treated with single agent ganetespib at 200 mg/m(2) once weekly for 3 weeks, on a 28-day cycle. Therapy was continued until disease progression. The primary end point was ORR using Reponse Evaluation Criteria in Solid Tumors version 1.1., Results: Twenty-two patients were enrolled with a median age of 51(range, 38-70) years and a median Eastern Cooperative Oncology Group performance status of 0 (range, 0-1). Most patients had at least 2 previous lines of chemotherapy in the metastatic setting. Most common toxicities, largely grade 1/2, were diarrhea, fatigue, nausea, and hypersensitivity reaction. The ORR in this unselected population was 9%, with all responses coming from the subset of patients with HER2-positive MBC (2/13; 15%). One patient with TNBC had objective tumor regression in the lung metastases. The clinical benefit rate (complete response + partial response + stable disease > 6 months) was 9%, median progression-free survival was 7 weeks (95% confidence interval [CI], 7-19), and median overall survival was 46 weeks (95% CI, 27-not applicable)., Conclusion: The study did not meet the prespecified criteria for ORR in the first stage of the Simon 2-stage model in this heavily pretreated unselected population of MBC. However, activity was observed in trastuzumab-refractory HER2-positive and TNBC. Ganetespib was well tolerated and responses in more targeted populations harboring specific HSP90-dependent oncoproteins justifies its further study, particularly as part of rational combinations., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Development of brain metastasis in patients with breast carcinoma correlates with poor outcome. Identification of tumor characteristics associated with breast cancer brain metastases (BCBM) could help identify patients at risk., Patients and Methods: We studied 209 patients with BCBM. We evaluated a panel of proteins relevant to the biology of breast carcinoma on tissue microarrays of 133 primary tumors and 56 BCBM, including paired samples from 43 patients, and correlated the findings with the clinical outcome., Results: The median survival after BCBM diagnosis was 19 months (95% confidence interval, 13-23 months). Patients presenting with solitary metastasis had a significantly longer median survival than those with multiple lesions (25 versus 11 months, P ≤ 0.0001). We found no significant discordance in the expression of tested markers, but identified a possible association between the expression of basal cytokeratin CK5/6 in the primary carcinoma and the development of multiple rather than solitary brain metastases., Conclusions: Expression of antigens commonly associated with breast carcinoma does not differ significantly between the primary tumor and the corresponding brain metastases. Although no specific immunoprofile identifies breast carcinomas that develop brain metastases, we observed a possible association between CK5/6 expression in the primary tumor and multiple versus solitary BCBM.

Ambient temperature exerts a prominent influence on sleep. In rats and humans, low ambient temperatures generally impair sleep, whereas higher temperatures tend to promote sleep. The purpose of the current study was to evaluate sleep patterns and core body temperatures of C57BL/6J mice at ambient temperatures of 22, 26 and 30 degrees C under baseline conditions, after sleep deprivation (SD), and after infection with influenza virus. C57BL/6J mice were surgically implanted with electrodes for recording electroencephalogram (EEG) and electromyogram (EMG) and with intraperitoneal transmitters for recording core body temperature (T(c)) and locomotor activity. The data indicate that higher ambient temperatures (26 and 30 degrees C) promote spontaneous slow wave sleep (SWS) in association with reduced delta wave amplitude during SWS in C57BL/6J mice. Furthermore, higher ambient temperatures also promote recuperative sleep after SD. Thus, in mice, higher ambient temperatures reduced sleep depth under normal conditions, but augmented the recuperative response to sleep loss. Mice infected with influenza virus while maintained at 22 or 26 degrees C developed more SWS, less rapid eye movement sleep, lower locomotor activity and greater hypothermia than did mice maintained at 30 degrees C during infection. In addition, despite equivalent viral titers, mice infected with influenza virus at 30 degrees C showed less leucopenia and lower cytokine induction as compared with 22 and 26 degrees C, respectively, suggesting that less inflammation develops at the higher ambient temperature.

The transfer of levonorgestrel (LNG) from the maternal plasma via breast milk to the infant was studied in 38 fully lactating and breast-feeding women at 4-6 weeks postpartum, for a duration of 28 days. These volunteers were provided with LNG contraceptive treatment delivered through three, different routes of drug delivery system: (i) intrauterine devices impregnated with LNG (LNG-IUD); (ii) subdermal implant (Norplant (R)-2); and (iii) minipills (LNG 30 micrograms daily). On the first day after either the LNG-IUD (n = 14 women) or Norplant (R)-2 (n = 14 women) insertion, the maternal blood and breast milk samples were collected at 2, 4 and 8 hourly intervals. This was followed by daily collection of these samples as well as infant's blood from days 2 to 4 and thereafter on days 7, 14 and 28. For infant's blood samples from LNG minipill users (n = 10 women), only a single 4-hour sample was collected on the first day and no samples were collected on days 3 and 4. The rest of the schedule for collection of maternal blood and breast milk as well as infant's blood samples were the same in minipill users as for the other two treatment groups. The study revealed a lower LNG percentage transfer from maternal sera to breast milk--11.8 +/- 2, 7 +/- 2 and 8 +/- 1 and relatively higher percentage LNG transfer from breast milk to infant's sera--75 +/- 17, 68 +/- 20 and 32 +/- 3, in LNG-IUD, Norplant (R)-2 and minipill users, respectively. Therefore, LNG contraceptive steroid is transferred into the infant's circulation, the biological significance of which remains to be established.