BACKGROUND:People with advanced cancer often experience a range of symptoms and reduced well-being. Experience sampling methods, which involve completing multiple smartphone-based questionnaires per day over several days, may offer detailed insights into how these experiences unfold in daily life. AIM:To evaluate feasibility and acceptability of experience sampling methods in advanced cancer, and its potential to uncover moment-to-moment symptom and well-being fluctuations. DESIGN:Observational study including baseline measurement, a 7-day experience sampling period with up to 10 assessments per day of symptoms and well-being, and follow-up measurement. We evaluated feasibility through response data and acceptability through a follow-up questionnaire measuring burden, ease-of-use, instruction clarity, and measurement reactivity. We analyzed fluctuations using within-person standard deviations. SETTING/PARTICIPANTS:We invited 79 people with advanced breast or lung cancer via two Belgian hospitals; 40 (51%) enrolled. RESULTS:Thirty-seven participants provided 1703 valid (71% of 2400 scheduled) experience sampling assessments. On 7-point scales, participants reported low burden (M = 2.1, SD = 0.8), high ease-of-use (M = 5.6, SD = 1.2) and instruction clarity (M = 6.5, SD = 0.5), and minimal measurement reactivity (M = 1.3, SD = 0.3). On 0-100 scales, we observed the greatest means of within-person fluctuations across days for tiredness (MiSD = 16.7, SD = 7.7), feeling relaxed (MiSD = 13.0, SD = 7.3), and activity limitations (MiSD = 12.4, SD = 9.9). Higher mean symptom intensity generally corresponded with greater within-person fluctuations. CONCLUSION:Experience sampling methods proved feasible and acceptable for people with advanced cancer, effectively capturing individuals' unique symptom and well-being fluctuations in daily life. The methods are a promising avenue to enhance personalized care and improve quality of life by revealing the mechanisms behind individuals' fluctuations.

PURPOSE:The Belgian Precision initiative aims to implement tumor-agnostic next-generation sequencing (NGS) in patients with advanced cancer and expand genotype-matching drug availability. The present investigator-driven trial aimed to study the efficacy of afatinib in patients with advanced solid tumors harboring an activating HER2, EGFR, or HER3 mutation. PATIENTS AND METHODS:This open-label phase II trial has three cohorts: HER2-, EGFR-, and HER3-mutated previously treated solid tumors. The primary end point was objective response rate (ORR). For each cohort, a Simon two-stage design was used. Observation of ≥2 responses in the first 10 patients prompted a further 19 to be included. Secondary end points were disease control rate (DCR), duration of response (DOR), progression-free survival, overall survival, and safety. RESULTS:A total of 45 patients were included, with a median age of 62 years. For the HER2 cohort (n = 30), ORR was 3.3% (one partial response) and DCR was 23.3%. In the EGFR cohort, a total of seven patients were included, resulting in an ORR in 2/7 (28.6%) patients, with a DOR of 6.6 and 15.4 months. In the HER3 cohort, a total of eight patients were included, but none demonstrated an objective response. Safety data were consistent with the known safety profile of afatinib. CONCLUSION:The present phase II study, investigating afatinib in HER2-, EGFR-, orHER3-mutant pretreated solid tumors did not reach its primary end point in the HER2 cohort. Neither the EGFR nor the HER3 cohort reached full accrual, but clinically meaningful responses were observed in two EGFR-mutated patients. Further exploration of HER targeting in solid tumors is warranted.

Understanding how to optimally measure symptoms and wellbeing of people with advanced cancer is crucial for supporting patient-centered care. We aimed to (1) compare repeated in-the-moment assessments (experience sampling methods/ESM) and retrospective assessments (traditional patient-reported outcome measures/PROMS) of symptoms and well-being among people with advanced breast or lung cancer; and (2) explore factors associated with discrepancies between these methods. In an observational study among people with advanced breast or lung cancer, participants completed up to 60 in-the-moment ESM assessments over 7 days, followed by a 7-day recall (i.e., retrospective) questionnaire covering the same period. We compared in-the-moment and retrospective scores of 16 symptom and wellbeing items visually and through correlations. We examined factors associated with discrepancies using linear regression. We analyzed 1676 in-the-moment assessments from 36 participants. Visually, higher in-the-moment scores were associated with higher retrospective scores across the sample. But, participants with identical retrospective scores often had different means (especially when they had higher recalled scores) and fluctuation patterns of in-the-moment scores. Item correlations between in-the-moment and retrospective scores ranged between .24 and .70. The largest discrepancies occurred for pain (Mdiff = −13.2) and tiredness (Mdiff = −12.4). Several parameters of in-the-moment scores and participants’ active treatment status were associated with discrepancies. Individuals’ retrospective symptom and wellbeing scores positively correlated with their in-the-moment scores over 1 week. Pain and tiredness showed the largest discrepancies. In-the-moment scores revealed considerable variability between individuals and fluctuations over time, which may be relevant to assess depending on the clinical or research objective.

Human epidermal growth factor receptor 2 (HER2) status is used for decision-making in breast carcinoma treatment. The status is obtained through immunohistochemistry or in situ hybridization. These two methods have the disadvantage of necessitating tissue sampling, which is prone to error due to tumor heterogeneity or interobserver variability. Whole-body imaging might be a solution to map HER2 expression throughout the body. Methods: Twenty patients with locally advanced or metastatic breast carcinoma (5 HER2-positive and 15 HER2-negative patients) were included in this phase II trial to assess the repeatability of uptake quantification and the extended safety of the [68Ga]Ga-NOTA-anti-HER2 single-domain antibody (sdAb). The tracer was injected, followed by a PET/CT scan at 90 min. Within 8 d, the procedure was repeated. Blood samples were taken for antidrug antibody (ADA) assessment and liquid biopsies. On available tissues, immunohistochemistry, in situ hybridization, and mass spectrometry were performed to determine the correlation of HER2 status with uptake values measured on PET. If relevant preexisting [18F]FDG PET/CT images were available (performed as standard of care), a comparison was made. Results: With a repeatability coefficient of 21.8%, this imaging technique was repeatable. No clear correlation between PET/CT uptake values and pathology could be established, as even patients with low levels of HER2 expression showed moderate to high uptake. Comparison with [18F]FDG PET/CT in 16 patients demonstrated that in 7 patients, [68Ga]Ga-NOTA-anti-HER2 shows interlesional heterogeneity within the same patient, and [18F]FDG uptake did not show the same heterogeneous uptake in all patients. In some patients, the extent of disease was clearer with the [68Ga]Ga-NOTA-anti-HER2-sdAb. Sixteen adverse events were reported but all without a clear relationship to the tracer. Three patients with preexisting ADAs did not show adverse reactions. No new ADAs developed. Conclusion: [68Ga]Ga-NOTA-anti-HER2-sdAb PET/CT imaging shows similar repeatability to [18F]FDG. It is safe for clinical use. There is tracer uptake in cancer lesions, even in patients previously determined to be HER2-low or -negative. The tracer shows potential in the assessment of interlesional heterogeneity of HER2 expression. In a subset of patients, [68Ga]Ga-NOTA-anti-HER2-sdAb uptake was seen in lesions with no or low [18F]FDG uptake. These findings support further clinical development of [68Ga]Ga-NOTA-anti-HER2-sdAb as a PET/CT tracer in breast cancer patients.

Background Among the 10% of pancreatic cancers that occur in a familial context, around a third carry a pathogenic variant in a cancer predisposition gene. Genetic studies of pancreatic cancer predisposition are limited by high mortality rates amongst index patients and other affected family members. The genetic risk for pancreatic cancer is often shared with breast cancer susceptibility genes, most notably BRCA2, PALB2, ATM and BRCA1. Therefore, we hypothesized that additional shared genetic etiologies might be uncovered by studying families presenting with both breast and pancreatic cancer. Methods Focusing on a multigene panel of 276 DNA Damage Repair (DDR) genes, we performed next-generation sequencing in a cohort of 41 families with at least three breast cancer cases and one pancreatic cancer. When the index patient with pancreatic cancer was deceased, close relatives (first or second-degree) affected with breast cancer were tested (39 families). Results We identified 27 variants of uncertain significance in DDR genes. A splice site variant (c.1605 + 2T > A) in the RAD17 gene stood out, as a likely loss of function variant. RAD17 is a checkpoint protein that recruits the MRN (MRE11-RAD50-NBS1) complex to initiate DNA signaling, leading to DNA double-strand break repair. Conclusion Within families with breast and pancreatic cancer, we identified RAD17 as a novel candidate predisposition gene. Further genetic studies are warranted to better understand the potential pathogenic effect of RAD17 variants and in other DDR genes.

The Belgian Precision initiative aims to maximize the implementation of tumor-agnostic NGS in patients with advanced cancer and enhance access to molecularly-guided treatment options (MGTOs). Academic tumor-agnostic basket phase 2 studies are part of this initiative. The current investigator-driven trial aimed to investigate olaparib efficacy in advanced cancers with a pathogenic or likely pathogenic mutation (germline or somatic) in a gene that plays a role in homologous recombination (HR). Open-label multi-cohort phase 2 study that examines the efficacy of olaparib in patients with an HR gene mutation in their tumor and failed SoC. Patients with a somatic or germline mutation in the same gene define a cohort. For each cohort, a Simon minimax two-stage design was used. If a response was observed in the first 13 patients, 14 additional patients were included (type I error rate of 5% and a power of 80% when the true response rate is 20%). Here, we report the results on four completed cohorts: patients with a BRCA1, BRCA2, CHEK2 or ATM mutation. The overall objective response rate across different tumor types was 11% in the BRCA1 (N=27) and 21% in the BRCA2 (N=27) mutated cohorts. Partial responses were seen in pancreatic cancer, gallbladder cancer, endocrine carcinoma of the pancreas and parathyroid cancer. One patient with a BRCA2 germline mutated colon cancer has an ongoing CR with 19+ months on treatment. mPFS in responding patients is 14+ months (5-34+ months). The clinical benefit rate was 63% in the BRCA1 and 46% in the BRCA2 mutated cohorts. No clinical activity was observed in the ATM (N=13) and CHEK2 (N=14) cohorts. Safety data were consistent with the known profile of olaparib. Olaparib showed efficacy in different cancer types harboring somatic or germline mutations in the BRCA1/2 genes but not in ATM and CHEK2. Patients with any cancer type harboring BRCA1/2 mutations should have access to olaparib with real-world documentation of efficacy in a retrospective register.

The Belgian Precision initiative aims to implement tumor-agnostic NGS in advanced cancer patients (pts) and enhance access to genotype-matching drugs. The current study aimed to investigate the efficacy of afatinib in advanced pre-treated solid cancers with an EGFR (excluding non-small cell lung cancer (NSCLC)), HER2 or HER3 mutation. Open-label phase 2 study including 3 cohorts for previously treated advanced cancers: EGFR, HER2 and HER3 mutated. The primary endpoint for each cohort was objective response rate (ORR). Response assessment was performed every 8 weeks. For each cohort, a Simon two-stage design was used. The null hypothesis that the true ORR is 10%, was tested against a one-sided alternative that the true ORR is 30%. If two or more ORR were observed in the first ten pts, 19 additional pts were included (type I error 5% and power 80%) Secondary endpoints were disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety. A total of 45 pts were included in the trial with median age 62 years. The EGFR cohort comprised 7 pts: 2 pancreas, 1 head and neck, 1 breast, 1 endocrine tumor, 1 cervix and 1 kidney. The HER2 cohort comprised 30 pts: 11 NSCLC, 8 breast, 3 cervix, 2 colorectal, 2 head and neck, 1 bladder, 1 kidney, 1 liver and 1 pancreas. The HER3 cohort comprised 8 pts: 2 breast, 2 pancreas, 1 colorectal, 1 head and neck, 1 esophagus and 1 stomach. ORR and DCR were respectively 28.6% and 42.9% in the EGFR cohort, 3% and 49% in the HER2 cohort and 0% and 62.5% in the HER3 cohort. Partial responses were observed in a HER2-mutated NSCLC (1/11) with a DOR of 8.5 months, an EGFR-mutated breast cancer (1/1) with a DOR of 6.6 months and an EGFR-mutated pancreas cancer (1/2) with a DOR of 15.4 months. PFS and OS data will be presented at the meeting Safety data were consistent with the known safety profile of afatinib. Although three pts demonstrated a clinical meaningful benefit, afatinib did not result in a significant ORR improvement in the HER2 cohort, which completed accrual. Recruitment was hampered by a lack of systematic agnostic NGS sequencing and the COVID epidemic. Broader and more systematic agnostic NGS would enable further exploration of HER inhibition in solid tumors

Background: The Belgian Precision initiative aims to maximize the implementation of tumor-agnostic next-generation sequencing in patients with advanced cancer and enhance access to molecularly guided treatment options. Academic tumor-agnostic basket phase II studies are part of this initiative. The current investigator-driven trial aimed to investigate the efficacy of olaparib in advanced cancers with a (likely) pathogenic mutation (germline or somatic) in a gene that plays a role in homologous recombination (HR). Patients and methods: This open-label, multi-cohort, phase II study examines the efficacy of olaparib in patients with an HR gene mutation in their tumor and disease progression on standard of care.Patients with a somatic or germline mutation in the same gene define a cohort. For each cohort, a Simon minimax two-stage design was used. If a response was observed in the first 13 patients, 14 additional patients were included. Here, we report the results on four completed cohorts: patients with a BRCA1, BRCA2, CHEK2 or ATM mutation.Results: The overall objective response rate across different tumor types was 11% in the BRCA1-mutated (n = 27) and 21% in the BRCA2-mutated (n = 27) cohorts. Partial responses were seen in pancreatic cancer, gallbladder cancer, endocrine carcinoma of the pancreas and parathyroid cancer. One patient with a BRCA2 germline-mutated colon cancer has an ongoing complete response with 19+ months on treatment. Median progression-free survival in responding patients was 14+ months (5-34+ months). The clinical benefit rate was 63% in the BRCA1-mutated and 46% in the BRCA2-mutated cohorts. No clinical activity was observed in the ATM (n = 13) and CHEK2 (n = 14) cohorts.Conclusion: Olaparib showed efficacy in different cancer types harboring somatic or germline mutations in the BRCA1/2 genes but not in ATM and CHEK2. Patients with any cancer type harboring BRCA1/2 mutations should have access to olaparib.

BACKGROUND/AIM:Immunotherapy with PD-1/PDL1 blocking monoclonal antibodies has improved survival compared to the standard-of-care chemotherapy for several malignancies at different stages of these malignancies. Due to several reasons, many cancer patients in medical need have no access to these drugs. In this study, we aimed to investigate whether a low dose of nivolumab could also lead to a therapeutic response.PATIENTS AND METHODS:Patients with advanced cancer were treated with a flat low dose of 10 mg of nivolumab IV every two weeks at no drug cost.RESULTS:Disease control was noted in nine of the 18 patients. Two patients achieved complete remission, two had prolonged partial remission, and five had stable disease, of these only two experienced adverse events.CONCLUSION:A flat low dose of nivolumab may have clinical activity and is a cheap therapeutic option in patients in medical need for whom standard-dose immune checkpoint inhibitors are not accessible for any reason.

Background: Human epidermal growth factor receptor 2 (HER2) status is an important predictive biomarker in breast cancer (BC). Tumor heterogeneity has been described, with changes in HER2 expression levels between lesions and over the disease course. HER2 expression is assessed on tissue biopsies, at primary diagnosis and in metastatic lesions. A whole-body imaging technique such as PET/CT could help understand expression levels in different lesions. A 68Ga-labeled single domain antibody (sdAb) targeting the HER2 receptor has been developed and proven safe (Keyaerts et al., 2016). Imaging is performed at 90 min post-injection (pi). We report results of a phase II trial to assess the repeatability of the technique in 20 patients and the correlation of tracer uptake with HER2 tissue expression of the lesions present at the time of imaging. Methods: Twenty patients (pts) with a locally advanced or metastatic BC with at least one lesion of minimum 12 mm were included. Pts were injected intravenously with a typical protein mass of 100 µg and a radioactive dose ranging from 98-168 MBq 68GaNOTA-anti-HER2 sdAb. PET/CT images were obtained at 90 min pi. A second tracer injection followed by PET/CT was done with a maximal interval of 8 days. To assess repeatability, up to 5 lesions per pt were selected, with no more than 2 in a single organ. Peak Standard Uptake Values (SUVpeak) of the lesions were measured on both scans and compared with a t-test and Bland-Altman Plots. Images were compared to other available medical or imaging data and interpreted considering the subject’s disease course. Serum and plasma samples were collected before injection and between 60 and 365 days pi and stored for future detection of anti-drug antibodies (ADA) and liquid biopsies analysis for the presence of HER2 amplification. Tissue samples were assessed by central labs using mass spectrometry, immunohistochemistry and in fluorescence situ hybridization. Results: Twenty women with BC (6 HER2+, 14 HER2-) with a mean age of 58.6 y (37-81) were included. Three pts were scanned only once (2 due to withdrawal of consent, 1 due to covid pandemic). Repeatability of the technique was visually scored as excellent. For quantification, 50 lesions were compared on both scans in 17 pts without significant differences between the two measurements (p=0.40). The repeatability coefficient (RC) was 38.2%. The mean absolute percentage difference (MAPD) was 13.6%, comparable to repeat values reported for 18F-FDG. In 3 out of 6 HER2-positive (HER2+) patients, lesions showed high uptake, even better visible than using 18F-FDG in 2 of them. In 2 HER2+ subjects with a negative scan, lesions were confirmed to be true negatives: one patient did not relapse from BC but had tuberculosis; the other was confirmed to have a radiopneumonitis after radiotherapy and no relapse. In 1 HER2+ patient, the uptake was unexpectedly low. However, the HER2 status was also not reconfirmed in the metastatic setting for this subject. In 1 HER2-negative patient, the tumor HER2 status was changed from negative to positive based on a subsequent image-guided biopsy performed in this study. High tracer uptake was also seen in many of the patients presenting with HER2-low BC (IHC 1+ or 2+), indicating the potential of the tracer to detect low-level HER2 expression. Additional correlation to centrally performed tissue and blood analysis is ongoing. Conclusion: 68GaNOTA-Anti-HER2 PET/CT shows high uptake in HER2-expressing BC lesions but also in HER2-low lesions. The technique shows good repeatability and, in some cases, even better sensitivity than 18F-FDG PET/CT. Specificity was confirmed in relapse-free lesions such as tuberculosis and radiopneumonitis. Its sensitivity makes it a promising technique to assess HER2+ and HER2-low lesions in BC patients. Citation Format: Odrade Gondry, Catarina Xavier, Wim Waelput, Omar Al Dabssi, Marian Vanhoeij, Sandrine Aspeslagh, Sofie Joris, Christel Fontaine, Guy Verfaillie, Jacques De Grève, Katrien Glorieus, Ine Luyten, Frederik Vandenbroucke, Sophie Bourgeois, Laurens Raes, Sheeno Thyparambil, Nick Devoogdt, Ilse Vaneycken, Julie Cousaert, Vicky Caveliers, Hendrik Everaert, Tony Lahoutte, Marleen Keyaerts. Assessment of repeatability and uptake quantification of 68GaNOTA-anti-HER2 sdAb PET/CT in patients with locally advanced or metastatic breast cancer [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 P3-02-05.

Objectives: To compare real life effectiveness and safety of nivolumab in patients with non-small cell lung cancer (NSCLC), according to age and Eastern Cooperative Group performance status (ECOG-PS). Methods: We performed a retrospective analysis of patients treated with nivolumab for NSCLC within a Belgian compassionate use program from July 2015 until December 2016. Safety and effectiveness were compared between patients aged >= 70 years and <70 years and between ECOG-PS 0/1 and >= 2. Results: A total of 324 patients with NSCLC were included. There was no significant difference between older (>= 70) and younger (<70 years) patients with regards to progression free survival (PFS) (4 months (95%CI 2.6;4.8) versus 3.7 months (95%CI 1; 7), p = 0.483) and overall survival (OS) (9.3 months (95% CI 5.5;13.1 months) versus 8.4 months (95%CI 6.3; 10.5), p= 0,638). Patients with an ECOG-PS >= 2 had a significant lower median PFS and OS compared to patients with an ECOG-PS 0-1 (2.2 (95%CI 1.4; 2.9) versus 5.6 months (95%CI 4.1; 7.1), p= 0.001 and 3.4 (95%CI 2.3; 4.5) versus 11.1 months (95%CI 8.9; 13.2), p b 0.001 respectively). No significant difference in all grades or grade 3/4 adverse events (AEs) were observed between the different age groups (p= 0.526 and p = 0.603 respectively). Patients with an ECOG-PS 0/1 had significantly more all grades AEs (p= 0.009) but no difference in grade 3/4 AEs was observed (p= 0.406) compared to ECOG-PS >= 2. Conclusion: This real life retrospective study confirms that safety and effectiveness of nivolumab is similar between different age groups, but that effectiveness is driven by performance status. (C) 2019 Elsevier Ltd. All rights reserved.

In the majority of familial breast cancer (BC) families, the etiology of the disease remains unresolved. To identify missing BC heritability resulting from relatively rare variants (minor allele frequency ≤ 1%), we have performed whole exome sequencing followed by variant analysis in a virtual panel of 492 cancer-associated genes on BC patients from BRCA1 and BRCA2 negative families with elevated BC risk. BC patients from 54 BRCA1 and BRCA2-negative families with elevated BC risk and 120 matched controls were considered for germline DNA whole exome sequencing. Rare variants identified in the exome and in a virtual panel of cancer-associated genes [492 genes associated with different types of (hereditary) cancer] were compared between BC patients and controls. Nonsense, frame-shift indels and splice-site variants (strong protein-damaging variants, called PDAVs later on) observed in BC patients within the genes of the panel, which we estimated to possess the highest probability to predispose to BC, were further validated using an alternative sequencing procedure. Exome- and cancer-associated gene panel-wide variant analysis show that there is no significant difference in the average number of rare variants found in BC patients compared to controls. However, the genes in the cancer-associated gene panel with nonsense variants were more than two-fold over-represented in women with BC and commonly involved in the DNA double-strand break repair process. Approximately 44% (24 of 54) of BC patients harbored 31 PDAVs, of which 11 were novel. These variants were found in genes associated with known or suspected BC predisposition (PALB2, BARD1, CHEK2, RAD51C and FANCA) or in predisposing genes linked to other cancer types but not well-studied in the context of familial BC (EXO1, RECQL4, CCNH, MUS81, TDP1, DCLRE1A, DCLRE1C, PDE11A and RINT1) and genes associated with different hereditary syndromes but not yet clearly associated with familial cancer syndromes (ABCC11, BBS10, CD96, CYP1A1, DHCR7, DNAH11, ESCO2, FLT4, HPS6, MYH8, NME8 and TTC8). Exome-wide, only a few genes appeared to be enriched for PDAVs in the familial BC patients compared to controls. We have identified a series of novel candidate BC predisposition variants/genes. These variants/genes should be further investigated in larger cohorts/case-control studies. Other studies including co-segregation analyses in affected families, locus-specific loss of heterozygosity and functional studies should shed further light on their relevance for BC risk.

BC patients vs. controls variant types enrichment in exome- and CAGP-wide. (XLSX 10 kb)

Adjuvant chemotherapy with docetaxel/cyclophosphamide (TC) is adopted worldwide as a valuable option for elderly patients with high-risk early breast cancer. Some studies suggest that paclitaxel may have a better therapeutic ratio than docetaxel. Therefore we have implemented an adjuvant chemotherapy in which docetaxel was replaced by paclitaxel. We report here the retrospective analysis of that cohort and make a safety comparison with an earlier TC cohort in the same target population. This retrospective analysis demonstrates the feasibility of paclitaxel/cyclophosphamide as an alternative, better tolerated adjuvant regimen for elderly patients. Further evaluation and assessment of noninferiority to TC is warranted.

PDAVs found in the CAPG of the 120 control samples and their occurrence in the general population. (XLSX 12 kb)

List with all genes (exome-wide) presenting a PDAV in at least two BC patients and the number of control samples presenting a PDAV in the same gene. (XLSX 12 kb)