Shallow whole genome sequencing approach to detect Homologous Recombination Deficiency in the PAOLA-1/ENGOT-OV25 phase-III trial.

The bevacizumab (bev)/olaparib (ola) maintenance regimen was approved for BRCA1/2-mutated (BRCAmut) and Homologous Recombination Deficient (HRD) high-grade Advanced Ovarian Cancer (AOC) first line setting, based on a significantly improved progression-free survival (PFS) compared to bev alone in the PAOLA-1/ENGOT-ov25 trial (NCT02477644), where HRD was detected by MyChoice CDx PLUS test. The academic shallowHRDv2 test was developed based on shallow whole-genome sequencing as an alternative to MyChoice. Analytical and clinical validities of shallowHRDv2 as compared to MyChoice on 449 PAOLA-1 tumor samples are presented. The overall agreement between shallowHRDv2 and MyChoice was 94% (369/394). Less non-contributive tests were observed with shallowHRDv2 (15/449; 3%) than with MyChoice (51/449; 11%). Patients with HRD tumors according to shallowHRDv2 (including BRCAmut) showed a significantly prolonged PFS with bev+ola versus bev (median PFS: 65.7 versus 20.3 months, hazard ratio (HR): 0.36 [95% CI: 0.24-0.53]). This benefit was significant also for BRCA1/2 wild-type tumors (40.8 versus 19.5 months, HR: 0.45 [95% CI: 0.26-0.76]). ShallowHRDv2 is a performant, clinically validated, and cost-effective test for HRD detection.

Efficacy of maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed, advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial.

OBJECTIVES: Adding maintenance olaparib to bevacizumab provided a significant progression-free survival (PFS) benefit in patients with newly diagnosed, advanced ovarian cancer in the randomized, double-blind PAOLA-1/ENGOT-ov25 trial (NCT02477644). We analyzed PFS by clinical risk and biomarker status. METHODS: Patients received olaparib 300 mg twice daily for up to 24 months plus bevacizumab 15 mg/kg every 3 weeks for up to 15 months in total, or placebo plus bevacizumab. This post hoc exploratory analysis evaluated PFS in patients classified as higher risk (stage III with upfront surgery and residual disease or neoadjuvant chemotherapy; stage IV) or lower risk (stage III with upfront surgery and no residual disease), and by biomarker status. RESULTS: Of 806 randomized patients, 74% were higher risk and 26% were lower risk. After a median 22.9 months of follow-up, PFS favored olaparib plus bevacizumab versus placebo plus bevacizumab in higher-risk patients (hazard ratio [HR] 0.60; 95% confidence interval [CI] 0.49-0.74) and lower-risk patients (0.46; 0.30-0.72). Olaparib plus bevacizumab provided a substantial PFS benefit versus bevacizumab alone in the homologous recombination deficiency (HRD)-positive subgroup (higher risk: HR 0.39; 95% CI 0.28-0.54 and lower risk: 0.15; 0.07-0.30), with 24-month PFS rates in lower-risk patients of 90% versus 43%, respectively (Kaplan-Meier estimates). CONCLUSIONS: In PAOLA-1, maintenance olaparib plus bevacizumab provided a substantial PFS benefit in HRD-positive patients with a reduction of risk of progression or death of 61% in the higher-risk group and of 85% in the lower-risk group compared with bevacizumab alone.

Toward PET/MRI as one-stop shop for radiotherapy planning in cervical cancer patients.

BACKGROUND: Radiotherapy (RT) planning for cervical cancer patients entails the acquisition of both Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). Further, molecular imaging by Positron Emission Tomography (PET) could contribute to target volume delineation as well as treatment response monitoring. The objective of this study was to investigate the feasibility of a PET/MRI-only RT planning workflow of patients with cervical cancer. This includes attenuation correction (AC) of MRI hardware and dedicated positioning equipment as well as evaluating MRI-derived synthetic CT (sCT) of the pelvic region for positioning verification and dose calculation to enable a PET/MRI-only setup. MATERIAL AND METHODS: 16 patients underwent PET/MRI using a dedicated RT setup after the routine CT (or PET/CT), including eight pilot patients and eight cervical cancer patients who were subsequently referred for RT. Data from 18 patients with gynecological cancer were added for training a deep convolutional neural network to generate sCT from Dixon MRI. The mean absolute difference between the dose distributions calculated on sCT and a reference CT was measured in the RT target volume and organs at risk. PET AC by sCT and a reference CT were compared in the tumor volume. RESULTS: All patients completed the examination. sCT was inferred for each patient in less than 5 s. The dosimetric analysis of the sCT-based dose planning showed a mean absolute error (MAE) of 0.17 ± 0.12 Gy inside the planning target volumes (PTV). PET images reconstructed with sCT and CT had no significant difference in quantification for all patients. CONCLUSIONS: These results suggest that multiparametric PET/MRI can be successfully integrated as a one-stop-shop in the RT workflow of patients with cervical cancer.

Adoptive cell therapy with tumor-infiltrating lymphocytes in patients with metastatic ovarian cancer: a pilot study.

Objective:Ovarian cancer (OC) is often diagnosed at an advanced stage with two thirds of patients experiencing recurrent disease with a poor prognosis. Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) has shown curative potential in malignant melanoma, but has only been investigated scarcely in other cancers. In this pilot study, we tested TIL based ACT in patients with metastatic OC. Methods:Six patients with progressive platinum-resistant metastatic OC were treated with an infusion of TIL preceded by standard lymphodepleting chemotherapy and followed by decrescendo intravenous interleukin-2 (IL-2). Primarily, the feasibility and tolerability of the treatment was assessed. Secondarily, disease control rate was described and immune responses against tumor cells were monitored. Results:Treatment was well tolerated with manageable toxicities. Four patients had stable disease for three months and two patients for five months with five patients having a decrease in target lesions. Progression was primarily due to new lesions while target lesions in general remained stable or in regression. Antitumor reactivity was observed in TIL infusion products from five patients but no antitumor reactivity was detectable in peripheral blood lymphocytes collected after treatment. High numbers of infused TIL expressed exhaustion markers including LAG3 and PD-1, and immunostaining of tumor tissue demonstrated substantial MHCII and PD-L1 expression. Conclusions:ACT with TIL in combination with decrescendo IL-2 is feasible in patients with metastatic OC. Early indications of clinical activity were found. However, TIL ACT efficacy was incomplete with possible involvement of the inhibitory immune checkpoint pathways LAG3/MHCII and PD1/PD-L1.

Respiratory motion prediction by using the adaptive neuro fuzzy inference system (ANFIS).

The quality of radiation therapy delivered for treating cancer patients is related to set-up errors and organ motion. Due to the margins needed to ensure adequate target coverage, many breast cancer patients have been shown to develop late side effects such as pneumonitis and cardiac damage. Breathing-adapted radiation therapy offers the potential for precise radiation dose delivery to a moving target and thereby reduces the side effects substantially. However, the basic requirement for breathing-adapted radiation therapy is to track and predict the target as precisely as possible. Recent studies have addressed the problem of organ motion prediction by using different methods including artificial neural network and model based approaches. In this study, we propose to use a hybrid intelligent system called ANFIS (the adaptive neuro fuzzy inference system) for predicting respiratory motion in breast cancer patients. In ANFIS, we combine both the learning capabilities of a neural network and reasoning capabilities of fuzzy logic in order to give enhanced prediction capabilities, as compared to using a single methodology alone. After training ANFIS and checking for prediction accuracy on 11 breast cancer patients, it was found that the RMSE (root-mean-square error) can be reduced to sub-millimetre accuracy over a period of 20 s provided the patient is assisted with coaching. The average RMSE for the un-coached patients was 35% of the respiratory amplitude and for the coached patients 6% of the respiratory amplitude.

Breathing adapted radiotherapy for breast cancer: comparison of free breathing gating with the breath-hold technique.

BACKGROUND AND PURPOSE: Adjuvant radiotherapy after breast-conserving surgery for breast cancer implies a risk of late cardiac and pulmonary toxicity. This is the first study to evaluate cardiopulmonary dose sparing of breathing adapted radiotherapy (BART) using free breathing gating, and to compare this respiratory technique with voluntary breath-hold. PATIENTS AND METHODS: 17 patients were CT-scanned during non-coached breathing manoeuvre including free breathing (FB), end-inspiration gating (IG), end-expiration gating (EG), deep inspiration breath-hold (DIBH) and end-expiration breath-hold (EBH). The Varian Real-time Position Management system (RPM) was used to monitor respiratory movement and to gate the scanner. For each breathing phase, a population based internal margin (IM) was estimated based on average chest wall excursion, and incorporated into an individually optimised three-field mono-isocentric wide tangential photon field treatment plan for each scan. The target included the remaining breast, internal mammary nodes and periclavicular nodes. RESULTS: The mean anteroposterior chest wall excursion during FB was 2.5mm. For IG and EG, the mean excursions within gating windows were 1.1 and 0.7 mm, respectively, whereas for DIBH and EBH the excursions were 4.1 and 2.6mm, respectively. For patients with left-sided cancer, the median heart volume receiving more than 50% of the prescription dose was reduced from 19.2% for FB to 2.8% for IG and 1.9% for DIBH, and the median left anterior descending (LAD) coronary artery volume was reduced from 88.9% to 22.4% for IG and 3.6% for DIBH. Simultaneously, the median ipsilateral relative lung volume irradiated to >50% of the prescribed target dose for both right- and left-sided cancers was reduced from 45.6% for FB to 29.5% for IG and 27.7% for DIBH. For EBH and EG, both the irradiated heart, LAD and lung volumes increased compared to FB. CONCLUSIONS: This is the first study to demonstrate the dosimetric benefits of free breathing gated breast cancer radiotherapy. IG compared favourably with DIBH, substantially reducing cardiac doses simultaneous with significant pulmonary tissue sparing.