Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a
mutation. The effect of combining maintenance olaparib and ...bevacizumab in patients regardless of
mutation status is unknown.
We conducted a randomized, double-blind, international phase 3 trial. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinum-taxane chemotherapy plus bevacizumab. Patients were eligible regardless of surgical outcome or
mutation status. Patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months; all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total. The primary end point was the time from randomization until investigator-assessed disease progression or death.
Of the 806 patients who underwent randomization, 537 were assigned to receive olaparib and 269 to receive placebo. After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 16.6 months with placebo plus bevacizumab (hazard ratio for disease progression or death, 0.59; 95% confidence interval CI, 0.49 to 0.72; P<0.001). The hazard ratio (olaparib group vs. placebo group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with tumors positive for homologous-recombination deficiency (HRD), including tumors that had
mutations (median progression-free survival, 37.2 vs. 17.7 months), and 0.43 (95% CI, 0.28 to 0.66) in patients with HRD-positive tumors that did not have
mutations (median progression-free survival, 28.1 vs. 16.6 months). Adverse events were consistent with the established safety profiles of olaparib and bevacizumab.
In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a
mutation. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644.).
The impact of single-agent antibodies against programmed death-ligand 1 (PD-L1) as maintenance therapy is unknown in patients with metastatic breast cancer. The SAFIR02-BREAST IMMUNO substudy ...included patients with human epidermal growth factor receptor type 2 (Her2)-negative metastatic breast cancer whose disease did not progress after six to eight cycles of chemotherapy. Patients (n = 199) were randomized to either durvalumab (10 mg kg
every 2 weeks) or maintenance chemotherapy. In the overall population, durvalumab did not improve progression-free survival (adjusted hazard ratio (HR): 1.40, 95% confidence interval (CI): 1.00-1.96; P = 0.047) or overall survival (OS; adjusted HR: 0.84, 95% CI: 0.54-1.29; P = 0.423). In an exploratory subgroup analysis, durvalumab improved OS in patients with triple-negative breast cancer (TNBC; n = 82; HR: 0.54, 95% CI: 0.30-0.97, P = 0.0377). Exploratory analysis showed that the HR of death was 0.37 (95% CI: 0.12-1.13) for patients with PD-L1
TNBC (n = 32) and 0.49 (95% CI: 0.18-1.34) for those with PD-L1
TNBC (n = 29). In patients with TNBC, exploratory analyses showed that the HR for durvalumab efficacy (OS) was 0.18 (95% CI: 0.05-0.71; log-rank test, P = 0.0059) in patients with CD274 gain/amplification (n = 23) and 1.12 (95% CI: 0.42-2.99; log-rank test, P = 0.8139) in patients with CD274 normal/loss (n = 32). Tumor infiltration by lymphocytes (CD8, FoxP3 and CD103 expressions) and homologous recombination deficiency did not predict sensitivity to durvalumab in exploratory analyses. This latter finding should be interpreted with caution since only one patient presented a germline BRCA mutation. The present study provides a rationale to evaluate single-agent durvalumab in maintenance therapy in patients with TNBC. Exploratory analyses identified CD274 amplification as a potential biomarker of sensitivity. Maintenance chemotherapy was more effective than durvalumab in patients with hormone receptor-positive and Her2-negative disease.
Background
Neurokinin (NK) 1 receptor antagonists (RAs), administered in combination with a 5‐hydroxytryptamine‐3 (5‐HT3) RA and dexamethasone (DEX), have demonstrated clear improvements in ...chemotherapy‐induced nausea and vomiting (CINV) prevention over a 5‐HT3RA plus DEX. However, studies comparing the NK1RAs in the class are lacking. A fixed combination of a highly selective NK1RA, netupitant, and the 5‐HT3RA, palonosetron (NEPA), simultaneously targets two critical antiemetic pathways, thereby offering a simple convenient antiemetic with long‐lasting protection from CINV. This study is the first head‐to‐head NK1RA comparative study in patients receiving anthracycline cyclophosphamide (AC) and non‐AC moderately emetogenic chemotherapy (MEC).
Materials and Methods
This was a pragmatic, multicenter, randomized, single‐cycle, open‐label, prospective study designed to demonstrate noninferiority of single‐dose NEPA to a 3‐day aprepitant regimen in preventing CINV in chemotherapy‐naive patients receiving AC/non‐AC MEC in a real‐life setting. The primary efficacy endpoint was complete response (no emesis/no rescue) during the overall (0–120 hour) phase. Noninferiority was achieved if the lower limit of the 95% confidence interval (CI) of the difference between NEPA and the aprepitant group was greater than the noninferiority margin set at −10%.
Results
Noninferiority of NEPA versus aprepitant was demonstrated (risk difference 9.2%; 95% CI, −2.3% to 20.7%); the overall complete response rate was numerically higher for NEPA (64.9%) than aprepitant (54.1%). Secondary endpoints also revealed numerically higher rates for NEPA than aprepitant.
Conclusion
This pragmatic study in patients with cancer receiving AC and non‐AC MEC revealed that a single dose of oral NEPA plus DEX was at least as effective as a 3‐day aprepitant regimen, with indication of a potential efficacy benefit for NEPA.
Implications for Practice
In the absence of comparative neurokinin 1 (NK1) receptor antagonist (RA) studies, guideline committees and clinicians consider NK1RA agents to be interchangeable and equivalent. This is the first head‐to‐head study comparing one NK1RA (oral netupitant/palonosetron NEPA) versus another (aprepitant) in patients receiving anthracycline cyclophosphamide (AC) and non‐AC moderately emetogenic chemotherapy. Noninferiority of NEPA versus the aprepitant regimen was demonstrated; the overall complete response (no emesis and no rescue use) rate was numerically higher for NEPA (65%) than aprepitant (54%). As a single‐dose combination antiemetic, NEPA not only simplifies dosing but may offer a potential efficacy benefit over the current standard‐of‐care.
Guidelines suggest that NK1RA agents are interchangeable. This article reports the first study comparing one NK1RA (oral NEPA netupitant/palonosetron) with another (aprepitant) in patients receiving chemotherapy.
Objective
Emotional competence (EC) is considered a substantial resource in the adjustment of cancer patients, especially via its effect on anxiety and depression symptoms. This research aimed at ...assessing the impact of intrapersonal EC in young women (≤45 years) with breast cancer (YWBC) on their specific quality of life (i.e. subjective experience related to daily difficulties and perceived repercussions of the disease and treatments) related to chemotherapy, via anxiety and depression symptoms.
Methods
Two hundred fifty YWBC from 24 French centers completed a self‐reported questionnaire after diagnosis (T1) and after the chemotherapy phase (T2), comprising the Young Women Breast Cancer Inventory, the Profile of EC and the Hospital Anxiety and Depression Scale. The indirect effect of EC (T1) on subjective experience (T2) via anxiety and depression symptoms (T2) was tested using regressions and the Macro PROCESS.
Results
Emotional competence predicted fewer anxiety and depression symptoms at T1 and T2, and a better subjective experience at T2 via fewer anxiety and depression symptoms. Depression symptoms appeared to be a stronger mediator than anxiety symptoms on four dimensions (Support from close relatives, feeling of couple cohesion, body image and sexuality, management of children and everyday life), whereas anxiety symptoms appeared to be a stronger mediator on two dimensions (negative affectivity and apprehension about the future, deterioration of relationships).
Conclusions
These results support the importance of developing psycho‐affective interventions to reinforce the EC of YWBC during chemotherapy in order to facilitate the cognitive and emotional processes necessary for a better adjustment and subjective experience.
Abstract
With the approval of new therapies targeting the PI3K pathway, the detection of PIK3CA mutations has become a key factor in treatment management for HR+/HER2− metastatic breast cancer (MBC). ...We developed multiplex digital PCR (dPCR) assays to detect and quantify PIK3CA mutations. A first screening assay allows the detection of 21 mutations, with a drop-off system targeting the 542–546 hotspot mutations combined with the simultaneous detection of N345K, C420R, H1047L and H1047R mutations. In the case of a positive result, a sequential strategy based on other assays that we have developped allows for precise mutation identification. Clinical validity was determined by analyzing plasma circulating free DNA (cfDNA) from 213 HR+/HER2− MBC samples, as well as DNA extracted from 97 available matched tumors from 89 patients. Our assays have shown reliable specificity, accuracy and reproducibility, with limits of blank of three and four droplets for the screening assay. Sixty-eight patients (32%) had at least one PIK3CA mutation detectable in their plasma, and we obtained 83.1% agreement between the cfDNA analysis and the corresponding tumors. The high sensitivity and robustness of these new dPCR assays make them well-suited for rapid and cost-effective detection of PIK3CA mutations in the plasma of MBC patients.
Supervised exercise dietary programs are recommended to relieve cancer-related fatigue and weight increase induced by adjuvant treatment of early breast cancer (EBC). As this recommendation lacks a ...high level of evidence, we designed a multicenter randomized trial to evaluate the impact of an Adapted Physical Activity Diet (APAD) education program on fatigue. We randomized 360 women with EBC who were receiving adjuvant chemotherapy and radiotherapy to APAD or usual care at eight French cancer institutions. Data were collected at baseline, end of chemotherapy, end of radiotherapy, and 6 months post-treatment. The primary endpoint was the general cancer-related fatigue score using the MFI-20 questionnaire. Fatigue correlated with the level of precariousness, but we found no significant difference between the two groups in terms of general fatigue (
= 0.274). The APAD arm has a smaller proportion of patients with confirmed depression at the end of follow-up (
= 0.052). A transient modification in physical activity levels and dietary intake was reported in the experimental arm. However, a mixed hospital- and home-based APAD education program is not enough to improve fatigue caused by adjuvant treatment of EBC. Cancer care centers should consider integrating more proactive diet-exercise supportive care in this population, focusing on precarious patients.
Erb-b2 receptor tyrosine kinase 2 (ERBB2)-activating mutations are therapeutically actionable alterations found in various cancers, including metastatic breast cancer (MBC). We developed multiplex ...digital PCR assays to detect and quantify ERBB2 mutations in circulating tumor DNA from liquid biopsies. We studied the plasma from 272 patients with hormone-receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) MBC to detect 17 ERBB2 mutations using a screening assay. The assay was developed on the three-color Crystal dPCR™ naica® platform with a two-step strategy for precise mutation identification. We found that nine patients (3.3%) harbored at least one ERBB2 mutation. The mutation rate was higher in patients with lobular histology (5.9%) compared to invasive breast carcinoma of no special type (2.6%). A total of 12 mutations were found with the following frequencies: L755S (25.00%), V777L (25.00%), S310Y (16.67%), L869R (16.67%), S310F (8.33%), and D769H (8.33%). Matched tumor samples from six patients identified the same mutations with an 83% concordance rate. In summary, our highly sensitive multiplex digital PCR assays are well suited for plasma-based monitoring of ERBB2 mutational status in patients with MBC.
Introduction
Cases of osteonecrosis of the jaw have been reported by dental surgeons to the pharmacovigilance center in Rennes, France, occurring among patients treated with palbociclib, a ...cyclin-dependent kinase 4/6 inhibitor. Although this event was not expected with the drug, a safety signal was raised. Describing a local case series, the aim of our study was to identify specific patterns that might suggest a triggering role for these drugs, and to discuss pathophysiological hypotheses.
Materials and methods
A retrospective case series of patients exposed to cyclin-dependent kinase 4/6 inhibitors between 2016 and 2020 with a diagnosis of osteonecrosis of the jaw at the Rennes Dental Care Center was analyzed. The descriptive analysis was conducted on patient demographics, breast cancer characteristics, osteonecrosis of the jaw, biological data, and exposure to cyclin-dependent kinase 4/6 inhibitors.
Results
We identified eight cases, most of them at stages 0–1 (62.5%). Four patients were still exposed to palbociclib at the time of diagnosis and four had discontinued the treatment before the diagnosis. Chronological imputability could not be excluded given the drug’s half-life and the variable intervals of dental monitoring from one patient to another. All patients had at least one dental osteonecrosis risk factor (including dental extraction, dentures, and denosumab exposure at the time of diagnosis). Neutropenia and mucositis were not systematically reported at the time of diagnosis. The anatomopathological characteristics were nonspecific.
Conclusion
We did not identify a specific pattern that could suggest a triggering role of palbociclib in the development of ONJ.
Cognitive impairment, especially verbal episodic memory and executive function impairments, has been considered to be a possible adverse effect of aromatase inhibitors (AI). This phase III open-label ...study compared the impact of tamoxifen and AI on verbal episodic memory (Rey auditory verbal learning test—RAVLT) and other cognitive functions (visual memory, psychomotor speed, and executive functions) after 6 and 12 months of treatment in breast cancer patients undergoing adjuvant hormonotherapy. Menopausal chemo-naïve patients with resectable breast cancer were randomly assigned (1:1) at the end of the radiotherapy to receive tamoxifen or AI. Neuropsychological assessments, self-reported quality of life, and depression assessments were performed at baseline, before any hormonal treatment, and at 6 and 12 months. Mixed design analysis models of variance was used to compare the evolution of the scores between the groups during follow-up. A total of 74 evaluable patients were enrolled (Tamoxifen arm,
n
= 37; AI arm,
n
= 37; letrozole
n
= 18; anastrozole
n
= 16; exemestane
n
= 3). The median age at inclusion was 61 years (range, minimum 49–maximum 69). The patient and breast cancer characteristics were well balanced between arms. After 6 months, no significant differential effect of AI or tamoxifen was observed on the RAVLT. Moreover, considering the other cognitive measures and the quality of life questionnaires, there were also no differences between the groups during the 1-year follow-up. In this study, AI has not demonstrated worse adverse effects on cognitive functions than tamoxifen during a 1-year follow-up
Purpose:
Genomic signatures, such as EndoPredict®, may help clinicians to decide which adjuvant treatment is the most appropriate.
Methods:
We propose the EndoPredict® assay for unclear cases of ...adjuvant treatment in patients treated in our comprehensive cancer center. We prospectively and retrospectively report the decision of adjuvant treatment before and after the EndoPredict® assay, respectively, compared to the PREDICT’s tool scores.
Results:
From November 2016 to March 2019, 159 breast cancer tumors were analyzed and presented before and after the EndoPredict® assay. Before the EndoPredict® results, clinicians recommended chemotherapy for 57 patients (57/159, 36%). A total of 108 patients (108/159, 68%) were classified as EPclin high-risk score. There was only a slight agreement between clinicians’ decisions and EPclin risk score. The EPclin score led to 37% changes in treatment (59/159); chemotherapy was favored in 80% of cases (47/59). The PREDICT tool recommended chemotherapy for 16 high-risk patients (16/159, 10%).
Conclusion:
Although genomic tests were developed in order to de-escalate adjuvant treatment, in our comprehensive cancer center the use of the EndoPredict® assay led to an increase in prescribed chemotherapy.
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