Efficacy of administration sequence: Sacituzumab Govitecan and Trastuzumab Deruxtecan in HER2-low metastatic breast cancer.

BACKGROUND: Current guidelines recommend that patients with HER2-low metastatic breast cancer (MBC) receive sequentially two antibody-drug conjugates (ADCs): Sacituzumab Govitecan (SG) and Trastuzumab Deruxtecan (T-DXd), despite a similar payload. However, the effectiveness of one after another is unknown. METHODS: ADC-Low is a multicentre, retrospective study evaluating the efficacy of SG and T-DXd, one after another, with or without intermediary lines of chemotherapy, in patients with HER2-low MBC. RESULTS: One hundred and seventy-nine patients were included: the majority with HR-negative tumours received SG first (ADC1) (n = 100/108) while most with HR-positive tumours received T-DXd first (n = 56/71). Median progression-free survival 2 was short: 2.7 months (95% CI: 2.4-3.3) in the whole population, respectively, 3.1 (95% CI: 2.6-3.6) and 2.2 months (95% CI: 1.9-2.7) for patients receiving T-DXd or SG second (ADC2). Intermediary lines of chemotherapy between ADC1 and ADC2 had no impact. Primary resistance to ADC2 occurred in 54.4% of patients. Certain patients showed initial response to ADC2. CONCLUSIONS: Clinical benefit of sequentially administered SG and T-DXd is limited for most patients. Nevertheless, a subset of patients might benefit-on the short term-from a second ADC. Additional studies are needed to identify patients who could benefit from two ADCs with similar payloads.

Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer.

Background: While deregulation of the cyclin D1-CDK4/6-retinoblastoma pathway is common in hormone receptor positive (HR+) breast cancer, Rb is usually intact in HR+ breast cancer, and targeted CDK 4/6 inhibitors that act upstream of Rb, are routinely being utilized in clinical practice. However, factors that can lead to clinical resistance to CDK 4/6 inhibitors are not known. Patients and methods: We identified patients who had pre- and post-genotyping in tissue and peripheral blood samples after receiving CDK 4/6 inhibitors. Genotyping was carried out in tumor tissue or blood collected before start of CDK 4/6 inhibitor and after disease progression on CDK 4/6 inhibitor, covering more than 90% of the coding region in RB1. Results: We identified detectable acquired RB1 mutations in circulating tumor DNA (ctDNA) after exposure to CDK4/6 inhibitor (palbociclib, palbociclib, ribociclib) for 5, 8, and 13 months, respectively, in three patients. The RB1 mutations included substitution in donor splicing site of exon 8 of the RB1 gene in patient #1; substitution in donor splicing site of exon 22 of RB1 gene, exon 19 deletion, exon 3 insertion in patient #2; and RB1 exon 16 H483Y mutation in patient #3. None of these RB1 mutations were present in the pre-CDK 4/6 specimen highlighting these molecular alterations, which lead to functional loss of Rb1, likely emerged under selective pressure from the CDK4/6 inhibitor potentially confering therapeutic resistance. Conclusion: This is the first clinical report to describe the emergence of somatic RB1 mutations after exposure to palbociclib or ribociclib, in patients with metastatic breast cancer. Further research is needed to validate these findings, identify how these mutations temporally emerge under selective pressure of CDK 4/6 inhibitor, and develop rational therapeutic strategies.

Alpelisib and fulvestrant in PIK3CA-mutated hormone receptor-positive HER2-negative advanced breast cancer included in the French early access program.

SOLAR-1 and BYLieve trials documented the efficacy of the PI3K-inhibitor alpelisib in pre-treated PIK3CA-mutant, hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC) patients. We report here real-life data of patients prospectively registered in the French alpelisib early access program (EAP) opened to PIK3CA-mutant HR+/HER2- ABC patients treated with alpelisib and fulvestrant. Primary endpoint was PFS by local investigators using RECIST1.1. Eleven centers provided individual data on 233 consecutive patients. Patients had received a median number of 4 (range: 1-16) prior systemic treatments for ABC, including CDK4/6 inhibitor, chemotherapy, fulvestrant and everolimus in 227 (97.4%), 180 (77.3%), 175 (75.1%) and 131 (56.2%) patients, respectively. After a median follow-up of 7.1 months and 168 events, median PFS was 5.3 months (95% CI: 4.7-6.0). Among 186 evaluable patients, CBR at 6 months was 45.3% (95% CI: 37.8-52.8). In multivariable analysis, characteristics significantly associated with a shorter PFS were age < 60 years (HR = 1.5, 95% CI = 1.1-2.1), >5 lines of prior treatments (HR = 1.4, 95% CI = 1.0-2.0) and the C420R PI3KCA mutation (HR = 4.1, 95% CI = 1.3-13.6). N = 91 (39.1%) patients discontinued alpelisib due to adverse events. To our knowledge, this is the largest real-life assessment of alpelisib efficacy. Despite heavy pre-treatments, patients derived a clinically relevant benefit from alpelisib and fulvestrant.

Factors Involved in Delaying Initiation of Adjuvant Chemotherapy After Breast Cancer Surgery.

BACKGROUND: Delays in initiating adjuvant chemotherapy after breast cancer surgery seems to have an impact on patients' risk of relapse and their survival rate. The aim of this retrospective study was to identify factors delaying initiation of adjuvant chemotherapy after breast surgery. MATERIAL AND METHODS: All patients undergoing surgical treatment for mammary cancer between June 2014 and June 2015 and receiving adjuvant chemotherapy were selected retrospectively. RESULTS: In multivariate analysis, 3 factors significantly delay initiation of adjuvant chemotherapy: a secondary procedure (odds ratio [OR], 6.67; P = .00012), inclusion in a therapeutic trial (OR, 8.46; P = .0013), and a positive HER2 status (OR, 3.02; P = .063 [statistically significant]). DISCUSSION: This study provides a brief overview of the population most likely to experience a delay in the initiation of their adjuvant chemotherapy after cancer surgery. Our findings should assist interventions during initial management.

First endogenous fungal endophthalmitis due to Fusarium dimerum: A severe eye infection contracted during induction chemotherapy for acute leukemia.

Endophthalmitis is a rare infection of the vitreous and/or aqueous. It can be bacterial or fungal. Exogenous endophthalmitis is the most common form and results from direct inoculation of a pathogen after eye surgery or penetrating trauma. Endophthalmitis can also be endogenous, secondary to disseminated infection. Fungal endophthalmitis is associated with poor prognosis and treatment is difficult given the low penetration of most of the antifungal agents available and the emergence of resistant filamentous fungi like Fusarium. To our knowledge, we describe the first endogenous fungal endophthalmitis due to Fusarium dimerum, a ubiquitous pathogen found in soil and plants. A 71-year-old woman, diagnosed with acute myeloid leukemia, was hospitalized for surveillance after induction chemotherapy. Prophylaxis by antibiotics and posaconazole was ongoing when she complained of pain and decreased vision in the left eye. A voluminous chorioretinal abscess developed and after multiple sterile aqueous humour samples, only vitrectomy allowed diagnosis with fungal hyphae seen on May-Grünwald Giemsa stained smear and positive cultures. The fungus was identified as Fusarium dimerum. The treatment, that included intravitreal injections of voriconazole and amphotericin B associated with systemic administration of voriconazole, allowed complete control of the infection. The source of this infection could not be confirmed despite the discovery of several possible infection sites including a periungual whitlow on the left hand and a lesion on a nail, from which samples were negative in microbiology laboratories. Unfortunately, damages of the retina were too important and the patient did not recover sight of her left eye.

Treatment and technical intervention time analysis of a robotic stereotactic radiotherapy system.

The purpose of this study is to obtain a better operational knowledge of Stereotactic Body Radiotherapy (SBRT) treatments with CyberKnife(r). An analysis of both In-room Times (IRT) and technical interventions of 5 years of treatments was performed, during which more than 1600 patients were treated for various indications, including liver (21%), lung (29%), intracranial (13%), head and neck (11%) and prostate (7%). Technical interventions were recorded along with the time of the failure, time to the intervention, and the complexity and duration of the repair. Analyses of Time Between Failures (TBF) and Service Disrupting TBF(disr) were performed. Treatment time data and variability per indication and following different system upgrades were evaluated. Large variations of IRTs were found between indications, but also large variations for each indication. The combination of the time reduction Tool (using Iris(r)) and Improved Stop Handling was of major impact to shortening of treatment times. The first implementation of the Iris collimator alone did not lead to significantly shorter IRTs for us except during prostate treatments. This was mostly due to the addition at the same time of larger rotational compensation for prostate treatments (58 instead of 1.58). Significant differences of duration between the first fraction and following fractions of a treatment, representing the necessity of defining imaging parameters and explanation to patients, were found for liver (12 min) and lung treatments using Xsight(r) Spine (5 min). Liver and lung treatments represent the longest IRT's and involve the largest variability's in IRT. The malfunction rate of the system followed a Weibull distribution with the shape and scale parameters of 0.8 and 39.7. Mean TBF(disr) was 68 work hours. 60 to 80% of the service disrupting interventions were resolved within 30-60 min, 5% required external intervention and 30% occurred in the morning. The presented results can be applied in the evaluation of the required machine time in order to implement robotic radiosurgery for different indications. The analytical distributions of IRTs and technical interruptions can be used for simulations.

The development of working memory: further note on the comparability of two models of working memory.

This paper is a set of reflections on Kemps, De Rammelaere, and Desmet's article (2000, this issue), in which the two models by Baddeley and Pascual-Leone are compared. First, some of the similarities and differences between the two models which we identified in a 1994 paper (de Ribaupierre & Bailleux, 1994) are briefly summarized and reexamined in the light of more recent work. Second, we debate the issue of whether each model makes a specific contribution to the explanation of some of Kemps et al.'s results, that is, of whether they can be considered to be complementary. Third, we argue for the necessity of theoretical task analyses, in view of the divergent results obtained in the two tasks used (the Corsi and the Peanut tasks), notably different developmental profiles, and an overall higher level of performance in the Corsi task. Finally, we briefly summarize a very similar study in which we also used Mr. Peanut with concurrent tasks in children and in young adults and in which we obtained rather different results. By comparing the experimental procedures used in the two studies, we contribute some exploratory hypotheses, while raising issues that can easily be generalized to other visuo-spatial working memory tasks.