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BRCA1 or BRCA2-mutated breast cancers are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum agents owing to deficiency in homologous recombination repair of DNA damage. In this trial, we compared veliparib versus placebo in combination with carboplatin and paclitaxel, and continued as monotherapy if carboplatin and paclitaxel were discontinued before progression, in patients with HER2-negative advanced breast cancer and a germline BRCA1 or BRCA2 mutation. BROCADE3 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 147 hospitals in 36 countries. Eligible patients (aged ≥18 years) had deleterious germline BRCA1 or BRCA2 mutation-associated, histologically or cytologically confirmed advanced HER2-negative breast cancer, an Eastern Cooperative Oncology Group performance status of 0–2, and had received up to two previous lines of chemotherapy for metastatic disease. Patients were randomly assigned (2:1) by interactive response technology by means of permuted blocks within strata (block size of 3 or 6) to carboplatin (area under the concentration curve 6 mg/mL per min intravenously) on day 1 and paclitaxel (80 mg/m2 intravenously) on days 1, 8, and 15 of 21-day cycles combined with either veliparib (120 mg orally twice daily, on days −2 to 5) or matching placebo. If patients discontinued carboplatin and paclitaxel before progression, they could continue veliparib or placebo at an intensified dose (300 mg twice daily continuously, escalating to 400 mg twice daily if tolerated) until disease progression. Patients in the control group could receive open-label veliparib monotherapy after disease progression. Randomisation was stratified by previous platinum use, history of CNS metastases, and oestrogen and progesterone receptor status. The primary endpoint was investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy analyses were done by intention to treat, which included all randomly assigned patients with a centrally confirmed BRCA mutation, and safety analyses included all patients who received at least one dose of velilparib or placebo. This study is ongoing and is registered with ClinicalTrials.gov, NCT02163694. Between July 30, 2014, and Jan 17, 2018, 2202 patients were screened, of whom 513 eligible patients were enrolled and randomly assigned. In the intention-to-treat population (n=509), 337 patients were assigned to receive veliparib plus carboplatin–paclitaxel (veliparib group) and 172 were assigned to receive placebo plus carboplatin–paclitaxel (control group). Median follow-up at data cutoff (April 5, 2019) was 35·7 months (IQR 24·9–43·6) in the veliparib group and 35·5 months (23·1–45·9) in the control group. Median progression-free survival was 14·5 months (95% CI 12·5–17·7) in the veliparib group versus 12·6 months (10·6–14·4) in the control group (hazard ratio 0·71 [95% CI 0·57–0·88], p=0·0016). The most common grade 3 or worse adverse events were neutropenia (272 [81%] of 336 patients in the veliparib group vs 143 [84%] of 171 patients in the control group), anaemia (142 [42%] vs 68 [40%]), and thrombocytopenia (134 [40%] vs 48 [28%]). Serious adverse events occurred in 115 (34%) patients in the veliparib group versus 49 (29%) patients in the control group. There were no study drug-related deaths. The addition of veliparib to a highly active platinum doublet, with continuation as monotherapy if the doublet were discontinued, resulted in significant and durable improvement in progression-free survival in patients with germline BRCA mutation-associated advanced breast cancer. These data indicate the utility of combining platinum and PARP inhibitors in this patient population. AbbVie.

Bulk transcriptomic analyses of high-grade serous ovarian cancer (HGSOC) so far have not uncovered potential drug targets, possibly because subtle, disease-relevant transcriptional patterns are overshadowed by dominant, non-relevant ones. Our aim was to uncover disease-outcome-related patterns in HGSOC transcriptomes that may reveal novel drug targets. Using consensus-independent component analysis, we dissected 678 HGSOC transcriptomes of systemic therapy naïve patients—sourced from public repositories—into statistically independent transcriptional components (TCs). To enhance c-ICA’s robustness, we added 447 transcriptomes from non-serous histotypes, low-grade serous, and non-cancerous ovarian tissues. Cox regression and survival tree analysis were performed to determine the association between TC activity and overall survival (OS). Finally, we determined the activity of the OS-associated TCs in 11 publicly available spatially resolved ovarian cancer transcriptomes. We identified 374 TCs, capturing prominent and subtle transcriptional patterns linked to specific biological processes. Six TCs, age, and tumor stage stratified patients with HGSOC receiving platinum-based chemotherapy into ten distinct OS groups. Three TCs were linked to copy-number alterations affecting expression levels of genes involved in replication, apoptosis, proliferation, immune activity, and replication stress. Notably, the TC identifying patients with the shortest OS captured a novel transcriptional pattern linked to synaptic signaling, which was active in tumor regions within all spatially resolved transcriptomes. The association between a synaptic signaling-related TC and OS supports the emerging role of neurons and their axons as cancer hallmark-inducing constituents of the tumor microenvironment. These constituents might offer a novel drug target for patients with HGSOC.

PurposeImmune checkpoint inhibitors can induce a T cell–mediated anti-tumor immune response in patients with melanoma. Visualizing T cell activity using positron emission tomography (PET) might allow early insight into treatment efficacy. Activated tumor–infiltrating T cells express the high-affinity interleukin-2 receptor (IL-2R). Therefore, we performed a pilot study, using fluorine-18-labeled IL-2 ([18F]FB-IL2 PET), to evaluate whether a treatment-induced immune response can be detected.MethodsPatients with metastatic melanoma received ~ 200 MBq [18F]FB-IL2 intravenously, followed by a PET/CT scan before and during immune checkpoint inhibitor therapy. [18F]FB-IL2 uptake was measured as standardized uptake value in healthy tissues (SUVmean) and tumor lesions (SUVmax). Response to therapy was assessed using RECIST v1.1. Archival tumor tissues were used for immunohistochemical analyses of T cell infiltration.ResultsBaseline [18F]FB-IL2 PET scans were performed in 13 patients. SUVmean at baseline was highest in the kidneys (14.2, IQR: 11.6–18.0) and liver (10.6, IQR: 8.6–13.4). In lymphoid tissues, uptake was highest in spleen (10.9, IQR: 8.8–12.4) and bone marrow (2.5, IQR: 2.1–3.0). SUVmax in tumor lesions (n = 41) at baseline was 1.9 (IQR: 1.7–2.3). In 11 patients, serial imaging was performed, three at week 6, seven at week 2, and one at week 4. Median [18F]FB-IL2 tumor uptake decreased from 1.8 (IQR: 1.7–2.1) at baseline to 1.7 (IQR: 1.4–2.1) during treatment (p = 0.043). Changes in [18F]FB-IL2 tumor uptake did not correlate with response. IL-2R expression in four archival tumor tissues was low and did not correlate with baseline [18F]FB-IL2 uptake. No [18F]FB-IL2-related side effects occurred.ConclusionPET imaging of the IL-2R, using [18F]FB-IL2, is safe and feasible. In this small patient group, serial [18F]FB-IL2-PET imaging did not detect a treatment-related immune response.Trial registrationClinicaltrials.gov: NCT02922283; EudraCT: 2014-003387.20

Background Clinical efficacy of the mTOR inhibitor everolimus is limited in breast cancer and regularly leads to side-effects including hyperglycemia. The AMPK inhibitor and anti-diabetic drug metformin may counteract everolimus-induced hyperglycemia, as well as enhancing anti-cancer efficacy. We investigated the glucose-dependent growth-inhibitory properties of everolimus, metformin and the combination in breast cancer cell lines. Methods The breast cancer cell lines MCF-7, MDA-MB-231 and T47D were cultured in media containing 11 mM or 2.75 mM glucose with 21% or 1% oxygen. Everolimus and metformin treated cells were subjected to cytotoxicity and clonogenic assays, western blotting, FACS and metabolic measurements. Results Everolimus was less effective in MCF7 cells under low glucose conditions compared to high glucose conditions (IC 50 of >50 nM vs 29.1 ± 1.4 nM) in a short-term survival assay, while sensitivity of MDA-MB-231 and T47D cells to everolimus was lost under low glucose conditions. In contrast, metformin was more effective in low than in high glucose conditions in MCF7 (IC 50 of 1.8 ± 1.2 mM vs >5 mM) and MDA-MB231 cells (1.5 ± 1.3 mM vs 2.6 ± 1.2 mM). Metformin sensitivity of T47D cells was independent of glucose concentrations. Everolimus combined with metformin additively inhibited cell survival, clonogenicity, mTOR signaling activity and mitochondrial respiration. These effects were not the result of enhanced autophagy or apoptosis induction. Similar results were observed under hypoxic conditions. Conclusion Metformin-induced effects are additive to the anti-proliferative and colony inhibitory properties of everolimus through inhibition of mitochondrial respiration and mTOR signaling. These results warrant further in vivo investigation of everolimus combined with metformin as a putative anti-cancer therapy.

Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. A pathologic response (primary objective) was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. A partial radiologic response (secondary objective) was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on magnetic resonance imaging. All patients completed treatment without severe toxicity (exploratory objective). At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. In-depth analysis of the loco-regional and systemic immune response (predefined exploratory objective) showed that monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints, efficacy in terms of pathologic response as primary endpoint, radiologic response as secondary outcome and safety and tolerability as exploratory endpoint, were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment. Immune checkpoint blockade (ICB) has shown promising activity in patients with advanced endometrial cancer, however its potential in the context of loco-regional disease remains unclear. Here the authors report the results of a phase I trial of neoadjuvant pembrolizumab (anti-PD1) in patients with mismatch repair deficient resectable endometrial cancer.

Colitis is a common, but poorly understood, adverse event of immune checkpoint inhibitors that are standard-of-care for an expanding range of cancer types. This explorative study aimed to describe the immune infiltrates in the colon from individuals developing checkpoint inhibitor colitis and compare them to well-known immunophenotypes of acute graft-versus-host disease, ulcerative colitis, and Crohn’s disease. Colon biopsies (n = 20 per group) of patients with checkpoint inhibitor colitis, acute graft-versus-host disease, ulcerative colitis and Crohn’s disease, all colitis treatment-naïve, and of individuals with a normal colon were analyzed using immunohistochemistry: CD8 for cytotoxic T cells, CD4 for T helper cells, and CD68 to identify cells of macrophage lineage. CD8 + T cell, CD4 + T cell, and CD68 + cell counts were performed. Cell infiltration was scored as scattered/patchy or band-like in the superficial and deep gut mucosa. Checkpoint inhibitor colitis was found to be heavily infiltrated by CD8 + T cells. Comparative analysis between groups showed that both CD8 + T cell counts (P < 0.01) and immune cell infiltration patterns in checkpoint inhibitor colitis were most similar to those observed in ulcerative colitis, with a deep band-like CD4 + T cell infiltration pattern and a superficial band-like CD68 + cell infiltration pattern in both. In conclusion, this is the first immunohistopathological study comparing infiltrate characteristics of checkpoint inhibitor colitis, acute graft-versus-host disease, ulcerative colitis, and Crohn’s disease. Checkpoint inhibitor colitis samples are heterogeneous, heavily infiltrated by CD8 + T cells, and show an immune cell infiltration pattern that is more similar to ulcerative colitis than to colonic acute graft-versus-host disease or colonic Crohn’s disease.

PurposeMetabolically active tumour volume (MATV) is a potential quantitative positron emission tomography (PET) imaging biomarker in melanoma. Accumulating data indicate that low MATV may predict increased chance of response to immunotherapy and overall survival. However, metastatic melanoma can present with numerous (small) tumour lesions, making manual tumour segmentation time-consuming. The aim of this study was to evaluate multiple semi-automatic segmentation workflows to determine reliability and reproducibility of MATV measurements in patients with metastatic melanoma.MethodsAn existing cohort of 64 adult patients with histologically proven metastatic melanoma was used in this study. 18F-FDG PET/CT diagnostic baseline images were acquired using a European Association of Nuclear Medicine (EANM) Research Limited–accredited Siemens Biograph mCT PET/CT system (Siemens Healthineers, Knoxville, USA). PET data were analysed using manual, gradient-based segmentation and five different semi-automatic methods: three direct PET image–derived delineations (41MAX, A50P and SUV40) and two based on a majority-vote approach (MV2 and MV3), without and with (suffix ‘+’) manual lesion addition. Correlation between the different segmentation methods and their respective associations with overall survival was assessed.ResultsCorrelation between the MATVs derived by the manual segmentation and semi-automated tumour segmentations ranged from R2 = 0.41 for A50P to R2 = 0.85 for SUV40+ and MV2+, respectively. Manual MATV segmentation did not differ significantly from the semi-automatic methods SUV40 (∆MATV mean ± SD 0.08 ± 0.60 mL, P = 0.303), SUV40+ (∆MATV − 0.10 ± 0.51 mL, P = 0.126), MV2+ (∆MATV − 0.09 ± 0.62 mL, P = 0.252) and MV3+ (∆MATV − 0.03 ± 0.55 mL, P = 0.615). Log-rank tests showed statistically significant overall survival differences between above and below median MATV patients for all segmentation methods with areas under the ROC curves of 0.806 for manual segmentation and between 0.756 [41MAX] and 0.807 [MV3+] for semi-automatic segmentations.ConclusionsSimple and fast semi-automated FDG PET segmentation workflows yield accurate and reproducible MATV measurements that correlate well with manual segmentation in metastatic melanoma. The most readily applicable and user-friendly SUV40 method allows feasible MATV measurement in prospective multicentre studies required for validation of this potential PET imaging biomarker for clinical use.

PET-based tumor delineation is an error prone and labor intensive part of image analysis. Especially for patients with advanced disease showing bulky tumor FDG load, segmentations are challenging. Reducing the amount of user-interaction in the segmentation might help to facilitate segmentation tasks especially when labeling bulky and complex tumors. Therefore, this study reports on segmentation workflows/strategies that may reduce the inter-observer variability for large tumors with complex shapes with different levels of user-interaction. Twenty PET images of bulky tumors were delineated independently by six observers using four strategies: (I) manual, (II) interactive threshold-based, (III) interactive threshold-based segmentation with the additional presentation of the PET-gradient image and (IV) the selection of the most reasonable result out of four established semi-automatic segmentation algorithms (Select-the-best approach). The segmentations were compared using Jaccard coefficients (JC) and percentage volume differences. To obtain a reference standard, a majority vote (MV) segmentation was calculated including all segmentations of experienced observers. Performed and MV segmentations were compared regarding positive predictive value (PPV), sensitivity (SE), and percentage volume differences. The results show that with decreasing user-interaction the inter-observer variability decreases. JC values and percentage volume differences of Select-the-best and a workflow including gradient information were significantly better than the measurements of the other segmentation strategies (p-value<0.01). Interactive threshold-based and manual segmentations also result in significant lower and more variable PPV/SE values when compared with the MV segmentation. FDG PET segmentations of bulky tumors using strategies with lower user-interaction showed less inter-observer variability. None of the methods led to good results in all cases, but use of either the gradient or the Select-the-best workflow did outperform the other strategies tested and may be a good candidate for fast and reliable labeling of bulky and heterogeneous tumors.

SummaryBackground Metformin use is associated with reduced cancer risk in epidemiological studies and has preclinical anti-cancer activity in ovarian cancer models. The primary objective of this phase I study was to determine the recommended phase II dose (RP2D) of metformin in combination with carboplatin/paclitaxel in patients with ovarian cancer. Secondary objectives were to describe safety and pharmacokinetics. Methods In this single-center trial the RP2D of metformin in combination with carboplatin area under the concentration-time curve (AUC) 6 and paclitaxel 175 mg/m2 every 3 weeks (q3w) in patients with advanced epithelial ovarian cancer was determined using a 3 + 3 escalation rule at three fixed dose levels: 500 mg three times daily (tds), 850 mg tds and 1000 mg tds. Metformin was commenced on day 3 of cycle 1 and continued until 3 weeks after the last chemotherapy administration. The RP2D was defined as the dose level at which 0 of 3 or ≤ 1 of 6 evaluable subjects experienced a metformin-related dose-limiting toxicity (DLT). Safety was assessed according to CTCAE v4.0. Plasma and serum samples for pharmacokinetic (PK) analyses were collected during treatment cycles 1 and 2. Results Fifteen patients with epithelial ovarian cancer and an indication for neo-adjuvant (n = 5) or palliative (n = 10) treatment were included. No DLTs were observed. Three patients discontinued study treatment during cycle 1 for other reasons than DLT. Six patients were treated at the RP2D of metformin 1000 mg tds. The most frequent low-grade toxicities were anemia, hypomagnesemia and diarrhea. Grade 3 adverse events (AEs) occurred in ten patients, most common were leucopenia (n = 4), thrombocytopenia (n = 3) and increased GGT (n = 3). There were no grade 4 AEs. Metformin increased the platinum (Pt) AUC (Δ22%, p = 0.013) and decreased the Pt clearance (Δ-28%, p = 0.013). Metformin plasma levels were all within the therapeutic range for diabetic patients (0.1–4 mg/L). Conclusion The RP2D of metformin in combination with carboplatin and paclitaxel in advanced ovarian cancer is 1000 mg tds. This is higher than the RP2D reported for combination with targeted agents. A potential PK interaction of metformin with carboplatin was identified.

Background Effective systemic treatments have revolutionized the management of patients with metastatic melanoma, including those with brain metastases. The extent to which these treatments influence disease trajectories close to death is unknown. Therefore, this study aimed to gain insight into provided treatments and healthcare consumption during the last 3 months of life in patients with melanoma brain metastases. Methods Retrospective, single-center study, including consecutive patients with melanoma brain metastases diagnosed between June-2015 and June-2018, referred to the medical oncologist, and died before November-2019. Patient and tumor characteristics, anti-tumor treatments, healthcare consumption, presence of neurological symptoms, and do-not-resuscitate status were extracted from medical charts. Results 100 patients were included. A BRAF- mutation was present in 66 patients. Systemic anti-tumor therapy was given to 72% of patients during the last 3 months of life, 34% in the last month, and 6% in the last week. Patients with a BRAF- mutation more frequently received systemic treatment during the last 3 (85% vs. 47%) and last month (42% vs. 18%) of life than patients without a BRAF- mutation. Furthermore, patients receiving systemic treatment were more likely to visit the emergency room (ER, 75% vs. 36%) and be hospitalized (75% vs. 36%) than those who did not. Conclusion The majority of patients with melanoma brain metastases received anti-tumor treatment during the last 3 months of life. ER visits and hospitalizations occurred more often in patients on anti-tumor treatment. Further research is warranted to examine the impact of anti-tumor treatments close to death on symptom burden and care satisfaction.