Open-label, phase II, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ER+/HER2- breast cancer and an ESR1 mutation after disease progression on prior therapies: ELAINE 2.

BACKGROUND: Acquired ESR1 mutations in estrogen receptor-positive (ER+) metastatic breast cancer (mBC) drive treatment resistance and tumor progression; new treatment strategies are needed. Lasofoxifene, a next-generation, oral, endocrine therapy and tissue-specific ER antagonist, provided preclinical antitumor activity, alone or combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in ESR1-mutated mBC. PATIENTS AND METHODS: In the open-label, phase II, ELAINE 2 trial (NCT04432454), women with ESR1-mutated, ER+/human epidermal growth factor receptor 2-negative (HER2-) mBC who progressed on prior therapies (including CDK4/6i) received lasofoxifene 5 mg/day and abemaciclib 150 mg b.i.d until disease progression/toxicity. The primary endpoint was safety/tolerability. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), and objective response rate (ORR). RESULTS: Twenty-nine women (median age 60 years) participated; all but one were previously treated with a CDK4/6i (median duration 2 years). The lasofoxifene-abemaciclib combination was well tolerated with primarily grade 1/2 treatment-emergent adverse events (TEAEs), most commonly diarrhea, nausea, fatigue, and vomiting. One patient (with no prior CDK4/6i) discontinued treatment due to grade 2 diarrhea. No deaths occurred during the study. Median PFS was 56.0 weeks [95% confidence interval (CI) 31.9 weeks-not estimable; ∼13 months]; PFS rates at 6, 12, and 18 months were 76.1%, 56.1%, and 38.8%, respectively. CBR at 24 weeks was 65.5% (95% CI 47.3% to 80.1%). In 18 patients with measurable lesions, ORR was 55.6% (95% CI 33.7% to 75.4%). ESR1-mutant circulating tumor DNA (ctDNA) allele fraction decreased from baseline to week 4 in 21/26 (80.8%) patients. CONCLUSIONS: Lasofoxifene plus abemaciclib had an acceptable safety profile, was well tolerated, and exhibited meaningful antitumor activity in women with ESR1-mutated, ER+/HER2- mBC after disease progression on prior CDK4/6i. Observed decreases in ESR1-mutant ctDNA with lasofoxifene concordant with clinical response suggest target engagement. If the ELAINE 2 findings are confirmed in the initiated, phase III, ELAINE 3 trial, these data could be practice-changing and help address a critical unmet need.

Margetuximab with retifanlimab as first-line therapy in HER2+/PD-L1+ unresectable or metastatic gastroesophageal adenocarcinoma: MAHOGANY cohort A.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric and gastroesophageal adenocarcinoma (GEA) is globally treated with chemotherapy plus trastuzumab. Novel therapeutic strategies strive to not only optimize efficacy, but also limit toxicities. In MAHOGANY cohort A, margetuximab, an Fc-engineered, anti-HER2 monoclonal antibody (mAb) was combined with retifanlimab, an anti-programmed cell death protein 1 mAb, in the first-line HER2-positive/programmed death-ligand 1 (PD-L1)-positive GEA. PATIENTS AND METHODS: MAHOGANY cohort A part 1 is a single-arm trial to evaluate margetuximab plus retifanlimab in patients with HER2 immunohistochemistry 3+, PD-L1-positive (combined positive score ≥1%), and non-microsatellite instability-high tumors. Primary objectives for cohort A were safety/tolerability and the confirmed objective response rate (ORR). RESULTS: As of 3 August 2021, 43 patients were enrolled and received margetuximab/retifanlimab. Nine grade 3 treatment-related adverse events (TRAEs) were reported in eight (18.6%) patients and eight serious TRAEs in seven (16.3%) patients. There were no grade 4/5 TRAEs. Three patients discontinued margetuximab/retifanlimab because of immune-related adverse events. The ORR by independent assessment was 53% [21/40 (95% confidence interval (CI) 36.1-68.5)], with a median duration of response of 10.3 months (95% CI 4.6-not evaluable); disease control rate was 73% [29/40 (95% CI 56.1-85.4)]. The study sponsor discontinued the study in advance of the planned enrollment when it became apparent that the study design would no longer meet the requirements for drug approval because of recent advances in the treatment of GEA. CONCLUSIONS: The chemotherapy-free regimen of combined margetuximab/retifanlimab as first-line treatment in double biomarker-selected patients demonstrated a favorable toxicity profile compared with historical outcomes using chemotherapy plus trastuzumab. The ORR observed in this study compares favorably versus ORR observed with other chemotherapy-free approaches.

Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer.

Background: Estrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer. Patients and methods: To identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patient-matched primary-metastatic tumors and 51 metastases, (ii) high coverage (>500×) comprehensive genomic profiling of 287-395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage (>5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots. Results: We identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 3' partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations. Conclusions: Collectively, these data indicate that N-terminal ESR1 fusions involving exons 6-7 are a recurrent driver of endocrine therapy resistance and are impervious to ER-targeted therapies.

Acarbosa y propofol: ¿una peligrosa combinación? / Acarbose and propofol: A dangerous combination?

La hepatotoxicidad es una complicación infrecuente tras el empleo de propofol, que puede ser potencialmente grave en caso de no realizarse un diagnóstico precoz. El propofol es un fármaco cada vez más empleado en la práctica diaria no solo en cirugía sino también en la sedación de procedimientos invasivos ambulatorios tales como la endoscopia. Acarbosa es un fármaco clásico en el tratamiento de la diabetes tipo 2 en estadios iniciales que puede causar de forma infrecuente hepatitis tóxica. Se presenta el caso de una paciente que sufrió una hepatitis aguda secundaria al empleo de propofol como anestesia oftalmológica, hepatitis probablemente potenciada por el uso previo de acarbosa. El cuadro se diagnosticó de forma precoz y se resolvió sin complicaciones. El conocimiento de esta complicación en el ámbito de la anestesiología se revela cada vez más importante para mejorar la valoración preanestésica de los pacientes que vayan a ser sedados con propofol y así evitar en lo posible su aparición (AU)

Hepatotoxicity is a rare complication following the use of propofol and can be potentially serious if an early diagnosis is not made. Propofol is being increasingly used in daily practice, not only in surgery, but also in outpatient sedation procedures, such as endoscopy. Acarbose is a well-known drug used in type 2 diabetes treatment, particularly in the early phase. A case is reported on a patient who suffered an acute hepatitis secondary to the use of propofol in ophthalmology surgery, a hepatitis probably enhanced by prior use of acarbose, a drug that also can cause hepatotoxicity. An early diagnosis and it was resolved without complications. This case could contribute to improve pre-anesthetic evaluation of patients who will be undergoing sedation with propofol in order to avoid the possible appearance of hepatitis (AU)

[Acarbose and propofol: a dangerous combination?]. / Acarbosa y propofol: ¿una peligrosa combinación?

Hepatotoxicity is a rare complication following the use of propofol and can be potentially serious if an early diagnosis is not made. Propofol is being increasingly used in daily practice, not only in surgery, but also in outpatient sedation procedures, such as endoscopy. Acarbose is a well-known drug used in type 2 diabetes treatment, particularly in the early phase. A case is reported on a patient who suffered an acute hepatitis secondary to the use of propofol in ophthalmology surgery, a hepatitis probably enhanced by prior use of acarbose, a drug that also can cause hepatotoxicity. An early diagnosis and it was resolved without complications. This case could contribute to improve pre-anesthetic evaluation of patients who will be undergoing sedation with propofol in order to avoid the possible appearance of hepatitis.

Proximal duodeno-jejunostomy for the safe management of the difficult duodenal stump

Seven patients with peptic ulcer disease had severe scarring of the duodenum, making its closure at the time of gastrectomy difficult. They were managed intraoperatively with proximal duodeno-jejunostomy as a means to avoid the catastrophic complication of disruption of the duodenal stump closure with its consequent peritonitis. The jejunum used for this anastomosis was an extension of the long limb of a Roux en Y which is brought up to perform the gastrojejunostomy. The end to end duodeno-jejunostomy is performed proximal to a side to side gastrojejunostomy, hence the name, proximal duodeno Jejunostomy. These seven patients had no unexpected immediate postoperative complications during the thirty days following surgery and were all discharged from the hospital well. During the same three and a half year period twenty five other patients were submitted to gastrectomy and had two duodenal stump leaks after conventional closures. One patient died and the other survived after prolonged intensive care stay. These differences were not statistically significant. These duodenojejunostomies are non-functional anastomoses and should consequently stricture, but in one patient it remained open and he developed bile reflux gastritis in spite of the Roux en Y gastrojejunostomy constructed to avoid this complication. These anastomoses should be constructed as stenotic as possible

Proximal duodeno-jejunostomy for the safe management of the difficult duodenal stump.

Seven patients with peptic ulcer disease had severe scarring of the duodenum, making its closure at the time of gastrectomy difficult. They were managed intraoperatively with proximal duodeno-jejunostomy as a means to avoid the catastrophic complication of disruption of the duodenal stump closure with its consequent peritonitis. The jejunum used for this anastomosis was an extension of the long limb of a Roux en Y which is brought up to perform the gastrojejunostomy. The end to end duodeno-jejunostomy is performed proximal to a side to side gastrojejunostomy, hence the name, proximal duodeno Jejunostomy. These seven patients had no unexpected immediate postoperative complications during the thirty days following surgery and were all discharged from the hospital well. During the same three and a half year period twenty five other patients were submitted to gastrectomy and had two duodenal stump leaks after conventional closures. One patient died and the other survived after prolonged intensive care stay. These differences were not statistically significant. These duodenojejunostomies are non-functional anastomoses and should consequently stricture, but in one patient it remained open and he developed bile reflux gastritis in spite of the Roux en Y gastrojejunostomy constructed to avoid this complication. These anastomoses should be constructed as stenotic as possible.

[The Beijing conference did not meet our expectations. Interview with Sergia Galvan]. / La conferencia de Beijing no lleno nuestras expectativas. Entrevista a Sergia Galvan.

PIP: An interview with a representative of two women's groups in the Dominican Republic to the International Conference on Women in Beijing expresses disappointment with the achievements of the Conference. The women's movement in the Dominican Republic is at a time of transition in which the importance of working with and influencing other agencies of the civil society and government has become clear. The nongovernmental organizations (NGOs) prepared for the Beijing Conference with a national report evaluating actions for women undertaken in the decade since the previous Conference and recommending additional actions. The document served as a reference for discussions in regional meetings and with specific groups of women. Another document containing the proposals of the Dominican NGOs was created. Representatives of the NGOs participated in discussions with the General Office for Promotion of Women, which officially represented the Dominican Republic in Beijing. In a general sense, the plan of action suggested by the Dominican Republic agreed with that of the women's movement, except that in the important areas of sexual and reproductive rights, the official position was that of the Catholic Church. The outlook for continuing cooperation between the NGOs and the government, represented by the General Office for Promotion of Women, does not appear promising. Such cooperation is not a strategy or policy of the government, and there is considerable resistance within the government to the movement. Latin American and Caribbean women contributed to Conference discussions on the themes of poverty, the impact of structural adjustment programs, reproduction and sexual rights, and violence. The results of the Conference did not meet expectations, largely because of the weight of conservative elements opposed to changes in gender relations. Results should be sought not in the rather weak and underfunded Plan of Action, but in the activities generated by the process.^ieng