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Patients with MYC rearranged (MYC-R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Previously, we demonstrated in a single-arm phase II trial (HOVON-130) that addition of lenalidomide to R-CHOP (R2CHOP) is well-tolerated and yields similar complete metabolic remission rates as more intensive chemotherapy regimens in literature. In parallel with this single-arm interventional trial, a prospective observational screening cohort (HOVON-900) was open in which we identified all newly diagnosed MYC-R DLBCL patients in the Netherlands. Eligible patients from the observational cohort that were not included in the interventional trial served as control group in the present risk-adjusted comparison. R2CHOP treated patients from the interventional trial (n = 77) were younger than patients in the R-CHOP control cohort (n = 56) (median age 63 versus 70 years, p = 0.018) and they were more likely to have a lower WHO performance score (p = 0.013). We adjusted for differences at baseline using 1:1 matching, multivariable analysis, and weighting using the propensity score to reduce treatment-selection bias. These analyses consistently showed improved outcome after R2CHOP with HRs of 0.53, 0.51, and 0.59, respectively, for OS, and 0.53, 0.59, and 0.60 for PFS. Thus, this non-randomized risk-adjusted comparison supports R2CHOP as an additional treatment option for MYC-R DLBCL patients.

Supplementary Data from Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments

Flow chart of patients with BRCA1/2 alterations submitted to the study team between September 2016 and December 2019, and reasons for drop-out, rejection or screen failure. Abbreviations: VUS = Variant of Unknown Significance, LOH = Loss of Heterozygosity.

Purpose:In breast cancer, pathologic complete response (pCR) to neoadjuvant systemic therapy (NST) is associated with favorable long-term outcome. Trastuzumab emtansine as additional adjuvant therapy improves recurrence-free survival of patients with HER2-positive breast cancer without pCR, but it is uncertain whether all patients without pCR need additional therapy. We evaluated the prognostic value of residual disease after trastuzumab-based NST in patients with HER2-positive breast cancer using Residual Cancer Burden (RCB), Neoadjuvant Response Index (NRI), and Neo-Bioscore.Experimental Design:We included patients with stage II or III HER2-positive breast cancer treated with trastuzumab-based NST and surgery at The Netherlands Cancer Institute between 2004 and 2016. RCB, NRI, and Neo-Bioscore were determined. Primary endpoint was 5-year recurrence-free interval (RFI). A 3% difference compared with the pCR group was considered acceptable as noninferiority margin on the 5-year RFI estimate, based on a proportional hazards model, and its lower 95% confidence boundary.Results:A total of 283 women were included. Median follow-up was 67 months (interquartile range 44–100). A total of 157 patients (56%) with pCR (breast and axilla) had a 5-year RFI of 92% (95% CI, 88–97); patients without pCR had a 5-year RFI of 80% (95% CI, 72–88). Patients with an RCB = 1 (N = 40, 15%), an NRI score between 0.75 and 0.99 (N = 30, 11%), or a Neo-Bioscore of 0 to 1 (without pCR; N = 28, 11%) have a 5-year RFI that falls within a predefined noninferiority margin of 3% compared with patients with pCR.Conclusions:The RCB, NRI, and Neo-Bioscore can identify patients with HER2-positive breast cancer with minimal residual disease (i.e., RCB = 1, NRI ≥ 0.75, or Neo-Bioscore = 0–1) after NST who have similar 5-year RFI compared with patients with pCR.

Pharmacokinetics: Z-endoxifen levels per taselisib dose level

Purpose:Extensive work in preclinical models has shown that microenvironmental cells influence many aspects of cancer cell behavior, including metastatic potential and their sensitivity to therapeutics. In the human setting, this behavior is mainly correlated with the presence of immune cells. Here, in addition to T cells, B cells, macrophages, and mast cells, we identified the relevance of nonimmune cell types for breast cancer survival and therapy benefit, including fibroblasts, myoepithelial cells, muscle cells, endothelial cells, and seven distinct epithelial cell types.Experimental Design:Using single-cell sequencing data, we generated reference profiles for all these cell types. We used these reference profiles in deconvolution algorithms to optimally detangle the cellular composition of more than 3,500 primary breast tumors of patients that were enrolled in the SCAN-B and MATADOR clinical trials, and for which bulk mRNA sequencing data were available.Results:This large data set enables us to identify and subsequently validate the cellular composition of microenvironments that distinguish differential survival and treatment benefit for different treatment regimens in patients with primary breast cancer. In addition to immune cells, we have identified that survival and therapy benefit are characterized by various contributions of distinct epithelial cell types.Conclusions:From our study, we conclude that differential survival and therapy benefit of patients with breast cancer are characterized by distinct microenvironments that include specific populations of immune and epithelial cells.

Supplementary Figure from Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment

Time to progression per patient in a swimmers plot (all patients, N=30)

This file contains details on all late grade {greater than or equal to} 2 esophageal adverse events (I) and esophageal metabolic activity six weeks post-treatment (II).

Purpose:Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers.Experimental Design:In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency–approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease ≥ 16 weeks).Results:Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P ≤ 0.001) or BRAF inhibitors (9% vs. 1%; P ≤ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup.Conclusions:Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer.

Purpose:The strategy of combining endocrine therapy with PI3K-mTOR inhibition has shown promise in estrogen receptor (ER)–positive breast cancer, but new agents and combinations with a better therapeutic index are urgently needed. Taselisib is a potent, selective, beta-isoform–sparing PI3 kinase inhibitor.Patients and Methods:30 patients with ER-positive, metastatic breast cancer who had failed prior endocrine therapy were treated with escalating doses of taselisib (2 or 4 mg in an intermittent or continuous schedule) combined with tamoxifen 20 mg once daily in this phase 1b study using a “rolling six” design.Results:Taselisib combined with tamoxifen was generally well tolerated, with treatment-emergent adverse events as expected for this class of drugs, including diarrhea (13 patients, 43%), mucositis (10 patients, 33%), and hyperglycemia (8 patients, 27%). No dose-limiting toxicities were observed. Objective responses were seen in 6 of 25 patients with RECIST-measurable disease (ORR 24%). Median time to disease progression was 3.7 months. Twelve of 30 patients (40%) had disease control for 6 months or more. Circulating tumor (ct)DNA studies using next-generation tagged amplicon sequencing identified early indications of treatment response and mechanistically relevant correlates of clinical drug resistance (e.g., mutations in KRAS, ERBB2) in some patients.Conclusions:Taselisib can be safely combined with tamoxifen at the recommended phase 2 dose of 4 mg given once daily on a continuous schedule. Preliminary evidence of antitumor activity was seen in both PIK3CA mutant and wild-type cancers. The randomized phase 2 part of POSEIDON (testing tamoxifen plus taselisib or placebo) is currently recruiting.

This file contains details on loco-regional control, progression free survival and overall survival split by treatment arm.

This file contains Supplementary Methods: radiotherapy details (I), treatment schedules (II), definition of Dose Limiting Toxicity (III) and a schedule of assessments (IV).

Supplementary data to Steenbruggen TG, van Seijen M, Janssen LM, van Ramshorst MS, van Werkhoven E, Vrancken Peeters MJTDF, et al. Prognostic value of residual disease after neoadjuvant therapy in HER2-positive breast cancer evaluated by Residual Cancer Burden, Neoadjuvant Response Index & Neo-Bioscore. Table S1, Table S2, Table S3, Table S4, Text and legend Figure S1

This file contains details on the pharmacokinetic profile (I) and parameters (II) of olaparib.

Purpose:To identify an MTD of olaparib, a PARP inhibitor, in combination with loco-regional radiotherapy with/without cisplatin for the treatment of non–small cell lung cancer (NSCLC).Patients and Methods:Olaparib dose was escalated in two groups: radiotherapy (66 Gy/24 fractions in 2.75 Gy/fraction) with and without daily cisplatin (6 mg/m2), using time-to-event continual reassessment method with a 1-year dose-limiting toxicity (DLT) period. The highest dose level with a DLT probability Results:Twenty-eight patients with loco-regional or oligometastatic disease (39%) were treated: 11 at olaparib 25 mg twice daily and 17 at 25 mg once daily. The lowest dose level with cisplatin was above the MTD due to hematologic and late esophageal DLT. The MTD without cisplatin was olaparib 25 mg once daily. At a latency of 1–2.8 years, severe pulmonary adverse events (AE) were observed in 5 patients across all dose levels, resulting in 18% grade 5 pulmonary AEs. Exploratory analyses indicate an association with the radiation dose to the lungs. At the MTD, olaparib reduced PAR levels by more than 95% and abolished radiation-induced PARylation. Median follow-up of survivors was 4.1 years. Two-year loco-regional control was 84%, median overall survival in patients with locally advanced NSCLC was 28 months.Conclusions:Combined mildly hypofractionated radiotherapy and low-dose daily cisplatin and olaparib was not tolerable due to esophageal and hematologic toxicity. Severe pulmonary toxicity was observed as well, even without cisplatin. More conformal radiotherapy schedules with improved pulmonary and esophageal sparing should be explored.

Supplementary Table from Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment

Supplementary Table 1

This file contains details on pulmonary function changes in diffusion tests (I) and spirometry tests (II), and the incidence of severe pulmonary adverse events by treatment arm (III).

Figure S1 from Prognostic Value of Residual Disease after Neoadjuvant Therapy in HER2-Positive Breast Cancer Evaluated by Residual Cancer Burden, Neoadjuvant Response Index, and Neo-Bioscore

Supplementary Methods Text

Supplementary Table from Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments

This file contains the radiation doses to organs at risk (I) and details on systemic treatment (II).

Supplementary Figure from Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments

This file contains details on DLT (I) and DLT probabilities according to TITE-CRM in the CCRT arm (II) and (SC)RT study arm (III).

Taselisib pharmacokinetics in combination with tamoxifen

PIK3CA mutations detected at baseline (in samples from 8 out of 30 patients)

Supplementary Legend

Penile cancer (PeCa) is rare, and the survival of patients with advanced disease remains poor. A better understanding of where treatment fails could aid the development of new treatment strategies.To describe the disease course after pelvic lymph node (LN) treatment for PeCa.We retrospectively analysed 228 patients who underwent pelvic LN treatment with curative intent from 1969 to 2016. The main treatment modalities were neoadjuvant chemotherapy, chemoradiation, and pelvic LN dissection.In the case of multiple recurrence locations, the most distant location was taken and recorded as follows: local (penis), regional (inguinal and pelvic LN), and distant (any other location). A competing risk analysis was used to calculate the time to recurrence per location, and a Kaplan-Meier analysis was used for overall survival (OS).The median follow-up of the surviving patients was 79 mo. The reason for pelvic treatment was pelvic involvement on imaging (29%), two or more tumour-positive inguinal LNs (61%), or inguinal extranodal extension (52%). More than half of the patients (61%) developed a recurrence. The median recurrence-free survival was 11 mo. The distribution was local in 9%, regional in 27%, and distant in 64% of patients. The infield control rate of nonsystemically treated patients was 61% (113/184). From the start of pelvic treatment, the median OS was 17 mo (95% confidence interval 12-22). After regional or distant recurrence, all but one patient died of PeCa with median OS after a recurrence of 4.4 (regional) and 3.1 (distant) mo. This study is limited by its retrospective nature.The prognosis of PeCa patients treated on their pelvis who recur despite locoregional treatment is poor. The tendency for systemic spread emphasises the need for more effective systemic treatment strategies.In this report, we looked at the outcomes of penile cancer patients in an expert centre undergoing various treatments on their pelvis. We found that survival is poor after recurrence despite locoregional treatment. Therefore, better systemic treatments are necessary.

Background Pertuzumab greatly improves pathologic complete response (pCR) rates in early stage HER2-positive breast cancer. Long-term benefit of pertuzumab, however, is less well established, as follow-up of the NEOSPHERE and APHINITY trials did not show clear improvement in overall survival, although patients with high risk of recurrence (e.g. node positive) appeared to benefit. Since its long-term benefit remains uncertain, we compared outcome of patients treated with or without pertuzumab in a quasi-random experiment using real-world data. Methods We identified all patients with stage II-III HER2-positive breast cancer in the Netherlands treated with neoadjuvant trastuzumab containing chemotherapy between November 2013 and January 2016 from the nationwide Netherlands Cancer Registry. During this period, reimbursement of pertuzumab in the Netherlands was pending and pertuzumab was only available as trial medication for patients in 37 hospitals that participated in the TRAIN-2 study. This setting created a unique opportunity to compare two quasi-random cohorts of patients treated with or without pertuzumab. We used logistic regression analysis to evaluate the association between pertuzumab use and pCR (ypT0/is, ypN0) and Kaplan-Meier estimates and Cox regression analysis for the association with overall survival (OS). Multivariate analyses included age, cT-status, cN-status, hormone receptor (HR) status and grade. Multiple imputation was used to impute missing data for multivariate analysis. Results We identified 1,124 eligible patients of whom 453 (40%) had received pertuzumab. Baseline characteristics were comparable with and without pertuzumab: 61% of tumors were cT2, 22% cT3, 66% were node positive and 62% ER and/or PR-positive. Grade was missing for 17% in patients treated with and 46% in patients treated without pertuzumab and therefor imputed. PCR in breast and axilla could be determined in 1,091 patients. Pertuzumab use improved pCR rates (65% vs 41%, adjusted odds ratio [aOR] 3.01; 95% confidence interval [CI] 2.29-3.97; p Conclusion This real-world quasi-experiment confirms the efficacy of pertuzumab to achieve a pCR in stage II and III HER2-positive breast cancer. In addition, these data suggest a small absolute overall survival benefit with pertuzumab, most prominently in hormone receptor negative and node positive tumors. Despite the unique setting of two quasi-random cohorts treated with or without pertuzumab and very similar baseline characteristics, residual confounding cannot be fully excluded. Breast cancer specific evaluation and translational work including central revision of tumor grade for missing cases is pending. pCR (%)3-yr OS (%)Ptzno PtzPtzno PtzaHR (95%CI)Overall65%41%98%95%0.61 (0.38-1.00)HR-positive51%32%98%97%0.70 (0.36-1.33)HR-negative86%55%97%92%0.54 (0.26-1.13)cN071%46%99%100%0.54 (0.14-2.00)cN+62%38%97%93%0.65 (0.39-1.09) Citation Format: Anna van der Voort, Marte Liefaard, Mette van Ramshorst, Erik van Werkhoven, Astrid Scholten, Jelle Wesseling, Marie-Jeanne Vrancken Peeters, Linda de Munck, Gabe Sonke. Pathologic complete response and 3-year survival with or without pertuzumab using real-world data of stage II and III HER2-positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-07.

Contains fulltext : 218275.pdf (Publisher’s version ) (Closed access) Contains fulltext : 218275pre.pdf (Author’s version preprint ) (Open Access) OBJECTIVE: To assess European Association of Urology guideline adherence on the surgical management of patients with T1 renal tumours and the effects of centralisation of care. PATIENTS AND METHODS: Retrospective data from all kidney tumours that underwent radical nephrectomy (RN) or partial nephrectomy (PN) in the period 2012-2016 from the British Association of Urological Surgeons Nephrectomy Audit were retrieved and analysed. We assessed total surgical hospital volume (HV; RN and PN performed) per centre, PN rates, complication rates, and completeness of data. Descriptive analyses were performed, and confidence intervals were used to illustrate the association between hospital volume and proportion of PN. Chi- squared and Cochran-Armitage trend tests were used to evaluate differences and trends. RESULTS: In total, 13 045 surgically treated T1 tumours were included in the analyses. Over time, there was an increase in PN use (39.7% in 2012 to 44.9% in 2016). Registration of the Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) complexity score was included in March 2016 and documented in 39% of cases. Missing information on postoperative complications appeared constant over the years (8.5-9%). A clear association was found between annual HV and the proportion of T1 tumours treated with PN rather than RN (from 18.1% in centres performing /=100 cases/year [high volume]), which persisted after adjustment for PADUA complexity. Overall and major (Clavien-Dindo grade >/=III) complication rate decreased with increasing HV (from 12.2% and 2.9% in low-volume centres to 10.7% and 2.2% in high-volume centres, respectively), for all patients including those treated with PN. CONCLUSION: Closer guideline adherence was exhibited by higher surgical volume centres. Treatment of T1 tumours using PN increased with increasing HV, and was accompanied by an inverse association of HV with complication rate. These results support the centralisation of kidney cancer specialist cancer surgical services to improve patient outcomes.

Summary Background The optimal chemotherapy backbone for dual HER2 blockade in the neoadjuvant setting for early breast cancer is unknown. We investigated whether the addition of anthracyclines would improve pathological complete response compared with a carboplatin–taxane regimen, when given in combination with the HER2-targeted agents trastuzumab and pertuzumab. Methods The TRAIN-2 study is an open-label, randomised, controlled, phase 3 trial being done in 37 hospitals in the Netherlands. We recruited patients aged 18 years or older with previously untreated, histologically confirmed stage II–III HER2-positive breast cancer. Patients were randomly allocated using central randomisation software (1:1 ratio) with minimisation without a random component, stratified by tumour stage, nodal stage, oestrogen receptor status, and age, to receive 5-fluorouracil (500 mg/m 2 ), epirubicin (90 mg/m 2 ), and cyclophosphamide (500 mg/m 2 ) every 3 weeks for three cycles followed by paclitaxel (80 mg/m 2 on days 1 and 8) and carboplatin (area under the concentration–time curve [AUC] 6 mg/mL per min on day 1 or optionally, as per hospital preference, AUC 3 mg/mL per min on days 1 and 8) every 3 weeks for six cycles, or to receive nine cycles of paclitaxel and carboplatin at the same dose and schedule as in the anthracycline group. Patients in both study groups received trastuzumab (6 mg/kg, loading dose 8 mg/kg) and pertuzumab (420 mg, loading dose 840 mg) concurrently with all chemotherapy cycles. The primary endpoint was the proportion of patients who achieved a pathological complete response in breast and axilla (ypT0/is ypN0) in the intention-to-treat population. Safety was analysed in patients who received at least one treatment cycle according to actual treatment received. This trial is registered with ClinicalTrials.gov, number NCT01996267, and follow-up for long-term outcome is ongoing. Findings Between Dec 9, 2013, and Jan 14, 2016, 438 patients were enrolled and randomly assigned to the two treatment groups (219 patients to each group), of whom 418 were evaluable for the primary endpoint (212 in the anthracycline group and 206 in the non-anthracycline group). The median follow-up for all patients was 19 months (IQR 16–23 months). A pathological complete response was recorded in 141 (67%, 95% CI 60–73) of 212 patients in the anthracycline group and in 140 (68%, 61–74) of 206 in the non-anthracycline group (p=0·95). One patient randomly allocated to the non-anthracycline group did receive anthracyclines and was thus included in the anthracycline group for safety analyses; therefore, for the safety analyses there were 220 patients in the anthracycline group and 218 in the non-anthracycline group. Serious adverse events were reported in 61 (28%) of 220 patients in the anthracycline group and in 49 (22%) of 218 in the non-anthracycline group. The most common adverse events of any cause were grade 3 or worse neutropenia (in 131 [60%] of 220 patients in the anthracycline group vs 118 [54%] of 218 in the non-anthracycline group), grade 3 or worse diarrhoea (26 [12%] vs 37 [18%]), and grade 2 or worse peripheral neuropathy (66 [30%] vs 68 [31%]), with no substantial differences between the groups. Grade 3 or worse febrile neutropenia was more common in the anthracycline group than in the non-anthracycline group (23 [10%] vs three [1%], p vs 0 of 218). One patient in the anthracycline group died because of a pulmonary embolism, which was possibly treatment related. Interpretation In view of the high proportion of pathological complete responses recorded in both groups and the fact that febrile neutropenia was more frequent in the anthracycline group, omitting anthracyclines from neoadjuvant treatment regimens might be a preferred approach in the presence of dual HER2 blockade in patients with early HER2-positive breast cancer. Long-term follow-up is required to confirm these results. Funding Roche Netherlands.

Purpose: To identify an MTD of olaparib, a PARP inhibitor, in combination with loco-regional radiotherapy with/without cisplatin for the treatment of non–small cell lung cancer (NSCLC). Patients and Methods: Olaparib dose was escalated in two groups: radiotherapy (66 Gy/24 fractions in 2.75 Gy/fraction) with and without daily cisplatin (6 mg/m2), using time-to-event continual reassessment method with a 1-year dose-limiting toxicity (DLT) period. The highest dose level with a DLT probability Results: Twenty-eight patients with loco-regional or oligometastatic disease (39%) were treated: 11 at olaparib 25 mg twice daily and 17 at 25 mg once daily. The lowest dose level with cisplatin was above the MTD due to hematologic and late esophageal DLT. The MTD without cisplatin was olaparib 25 mg once daily. At a latency of 1–2.8 years, severe pulmonary adverse events (AE) were observed in 5 patients across all dose levels, resulting in 18% grade 5 pulmonary AEs. Exploratory analyses indicate an association with the radiation dose to the lungs. At the MTD, olaparib reduced PAR levels by more than 95% and abolished radiation-induced PARylation. Median follow-up of survivors was 4.1 years. Two-year loco-regional control was 84%, median overall survival in patients with locally advanced NSCLC was 28 months. Conclusions: Combined mildly hypofractionated radiotherapy and low-dose daily cisplatin and olaparib was not tolerable due to esophageal and hematologic toxicity. Severe pulmonary toxicity was observed as well, even without cisplatin. More conformal radiotherapy schedules with improved pulmonary and esophageal sparing should be explored.

Background: Histotype specific neoadjuvant therapy response data is scarce in soft tissue sarcomas. This study aimed to assess the impact of a moderate radiotherapy (RT) dose on resectability and to correlate MRI parameters to pathological treatment response in Myxoid Liposarcoma (MLS).Methods: This prospective, multicenter, single-arm, phase 2 trial assessed the radiological effects of 36 Gy of preoperative radiotherapy in primary non-metastatic MLS (n=34). Distance of the tumor to the neurovascular bundle, tumor dimensions, fat fraction, enhancing fraction were determined on MRI scans at baseline, after 8 and 16 fractions, and preoperatively. Pathological response was established by central pathology review.Results: Preoperative radiotherapy resulted in a median increase of 2 mm (IQR 0 to 6) of the distance of the tumor to the neurovascular bundle. As compared to baseline, the median change of the tumor volume, craniocaudal diameter and axial diameter at preoperative MRI were -60% (IQR -74 to -41), -19% (IQR -23 to -7) and -20% (IQR -29 to -12), respectively. The median fat fraction of 0.1 (IQR 0.0-0.1) and enhancing fraction of 0.8 (IQR 0.6 to 0.9) at baseline, changed to 0.2 (IQR 0.1 to 0.5) and to 0.5(IQR 0.4 to 0.9) preoperatively, respectively. Radiological signs of response in terms of volume, enhancing fraction and fat fraction were correlated with specific pathological signs of response like hyalinization, necrosis and fatty maturation.Conclusions: A moderate dose of preoperative radiotherapy may improve resectability in MLS and could facilitate achievement of clear margins and function preservation. MRI features which were predictive for expressions of pathological response, can play a role in further personalization of neoadjuvant treatment strategies in order to improve outcome in MLS. (C) 2021 Elsevier Ltd, BASO - The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Aim Oligometastatic breast cancer (OMBC) is a disease-entity with potential for long-term remission in selected patients. Those with truly limited metastatic load (rather than occult widespread metastatic disease) may benefit from multimodality treatment including local ablative therapy of distant metastases. In this systematic review, we studied factors associated with long-term survival in patients with OMBC. Methods Eligible studies included patients with OMBC who received a combination of local and systemic therapy as multimodal approach and reported overall survival (OS) or progression-free survival (PFS), or both. The Quality in Prognosis Studies (QUIPS) tool was used to assess the quality of each included study. Independent prognostic factors for OS and/or PFS are summarized. Results Of 1271 screened abstracts, 317 papers were full-text screened and twenty studies were included. Eleven of twenty studies were classified as acceptable quality. Definition of OMBC varied between studies and mostly incorporated the number and/or location of metastases. The 5-year OS ranged between 30 and 79% and 5-year PFS ranged between 25 and 57%. Twelve studies evaluated prognostic factors for OS and/or PFS in multivariable models. A solitary metastasis, >24 months interval between primary tumor and OMBC, no or limited involved axillary lymph nodes at primary diagnosis, and hormone-receptor positivity were associated with better outcome. HER2-positivity was associated with worse outcome, but only few patients received anti-HER2 therapy. Conclusions OMBC patients with a solitary distant metastasis and >24 months disease-free interval have the best OS and may be optimal candidates to consider a multidisciplinary approach.

Background Awareness of model-based designs for dose-finding studies such as the Continual Reassessment Method (CRM) is now becoming more commonplace amongst clinicians, statisticians and trial management staff. In some settings toxicities can occur a long time after treatment has finished, resulting in extremely long, interrupted, CRM design trials. The Time-to-Event CRM (TiTE-CRM), a modification to the original CRM, accounts for the timing of late-onset toxicities and results in shorter trial duration. In this article, we discuss how to design and deliver a trial using this method, from the grant application stage through to dissemination, using two radiotherapy trials as examples. Methods The TiTE-CRM encapsulates the dose-toxicity relationship with a statistical model. The model incorporates observed toxicities and uses a weight to account for the proportion of completed follow-up of participants without toxicity. This model uses all available data to determine the next participant’s dose and subsequently declare the maximum tolerated dose. We focus on two trials designed by the authors to illustrate practical issues when designing, setting up, and running such studies. Results In setting up a TiTE-CRM trial, model parameters need to be defined and the time element involved might cause complications, therefore looking at operating characteristics through simulations is essential. At the grant application stage, we suggest resources to fund statisticians’ time before funding is awarded and make recommendations for the level of detail to include in funding applications. While running the trial, close contact of all involved staff is required as a dose decision is made each time a participant is recruited. We suggest ways of capturing data in a timely manner and give example code in R for design and delivery of the trial. Finally, we touch upon dissemination issues while the trial is running and upon completion. Conclusion Model-based designs can be complex. We hope this paper will help clinical trial teams to demystify the conduct of TiTE-CRM trials and be a starting point for using this methodology in practice.

Background and purpose To investigate associations of early post-treatment 18Fluorodeoxyglucose-positron-emission-tomography (FDG-PET)-scans with local (LF), regional (RF), distant failure (DF) and overall survival (OS) in locally advanced non-small cell lung cancer (LA-NSCLC)-patients treated with concurrent chemoradiotherapy. Materials and methods Forty-seven stage IIIA-B NSCLC-patients included in a randomized phase II-trial (NTR2230) received 66 Gy (24x2.75 Gy) with low dose Cisplatin +/− Cetuximab. FDG-PET-scans were performed at baseline and 4 weeks post-treatment (range, 1.6–10.1). SUVmax, SUVmean, metabolic tumor volume (MTV), total lesion glycolysis (TLG) and gross tumor volume were calculated separately for the primary tumor and the involved lymph nodes to generate baseline, post-treatment, and relative response metrics defined as (metricpre-metricpost)/metricpre. Univariable cox regression analyses were performed to investigate associations between PET-metrics and outcomes. Results Metrics resulted from the post-treatment scan and relative response were associated with outcome, but baseline metrics were not. Primary tumor metrics were stronger associated with all outcomes than lymph node metrics. Both the volumetric (TLG/MTV) and intensity (SUVmax/SUVmean) PET-metrics were associated with OS. The intensity metrics were associated with LF, while the volumetric PET-metrics were associated with RF/DF. This was in contrast to the nodal metrics, demonstrating only an association between RF and the relative response of TLG/MTV. No preference was found between PET volumetric and intensity metrics associated with outcome. Conclusion Early post-treatment PET-metrics are associated with treatment outcome in LA-NSCLC patients treated with chemoradiotherapy. Both volumetric and intensity PET-metrics are useful, but more for the primary tumor than for lymph nodes.

Introduction: Uretero-ileal strictures (UES) following urinary diversion are therapeutically challenging. We compared the efficacy, safety and renal outcome following therapeutic endo-urological techniques (EUTs) and open surgical revision of the anastomosis (SRA) for UES. Material and Methods: We retrospectively analysed all EUTs and SRAs performed for UES in 2 hospitals between 1987 and 2015. Restenosis was defined as recurrent radiographically diagnosed hydronephrosis and re-intervention. Renal function (estimated glomerular filtration rate [eGFR]) decrease was correlated with the number of EUTs per patient. Results: Eighty-five UES were treated with 105 EUTs and 31 open revisions. Due to total obstruction, 28 (27%) EUTs were aborted. During a median follow-up of 33 months, restenosis occurred following 53 out of 77 (69%) completed EUTs and 4 out of 31 (13%) SRAs (p < 0.001 on univariable and multivariable analyses). No serious (Clavien ≥3b) EUT-related complications occurred vs. 5 (19%) related to SRA (p < 0.001). The number of finalised EUTs was independently associated with eGFR loss (β = 12.3 mL/min/1.73 m2 loss per EUT, p = 0.008), with a significant cutoff value of >1 EUTs. SRA did not affect renal function (β = 6.8 mL/min/1.73 m2 loss, p = 0.276). Conclusions: Although EUTs are less invasive, they have an inferior efficacy to SRA. Our results suggest that a maximum of one EUT may be attempted without significantly compromising renal function.

To this day, targeted treatment options for patients with triple negative metastatic breast cancer (TNBC) are still virtually absent. Previously, we showed that elevated expression of the tyrosine kinase FER is an independent prognosticator that correlates with poor survival of high-grade and basal/TNBC patients. Here, we show that high FER levels are also associated with improved outcome after adjuvant taxane-based combination chemotherapy, in high-risk, HER2-negative patients. In TNBC cells, we observed a causal relation between high FER levels and sensitivity to taxanes. Our proteomics and mechanistic studies demonstrated that FER regulates endosomal recycling, a microtubule-dependent process that underpins breast cancer cell invasion. Using chemical genetics, we identified DCTN2 as a novel FER substrate. Our work indicates that the DCTN2 tyrosine 6 is essential for tubular recycling domains development in early endosomes and subsequent propagation of TNBC cell invasion in 3D. In conclusion, we show that high FER expression promotes endosomal recycling and represents a candidate predictive marker for benefit of adjuvant taxane-containing chemotherapy in high-risk patients, including TNBC patients. Citation Format: Sandra Tavares, Nalan Liv, Milena Pasolli, Mark Opdam, Max Ratze, Manuel Saornil, Lilian Sluimer, Rutger Hengeveld, Robert van Es, Erik van Werkhoven, Harmjan Vos, Holger Rehmann, Boudewijn Burgering, Hendrika Oosterkamp, Susanne Lens, Judith Klumperman, Sabine Linn, Patrick Derksen. FER regulates endosomal recycling and is a candidate predictor for taxane benefit in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB203.

Importance Primary analysis of the TRAIN-2 study showed high pathologic complete response rates after neoadjuvant chemotherapy with or without anthracyclines plus dualERBB2(formerlyHER2) blockade. Objective To evaluate 3-year event-free survival (EFS) and overall survival (OS) of an anthracycline-free and anthracycline-containing regimen with dualERBB2blockade in patients with stage II and IIIERBB2-positive breast cancer. Design, Setting, and Participants A total of 438 patients with stage II and IIIERBB2-positive breast cancer were enrolled in this randomized, clinical, open-label phase 3 trial across 37 hospitals in the Netherlands from December 9, 2013, until January 14, 2016. Follow-up analyses were performed after a median follow-up of 48.8 months (interquartile range, 44.1-55.2 months). Analysis was performed on an intention-to-treat basis. Interventions Participants were randomly assigned on a 1:1 basis, stratified by age, tumor stage, nodal stage, and estrogen receptor status, to receive 3 cycles of fluorouracil (500 mg/m2), epirubicin (90 mg/m2), and cyclophosphamide (500 mg/m2), followed by 6 cycles of paclitaxel and carboplatin or 9 cycles of paclitaxel (80 mg/m2days 1 and 8) and carboplatin (area under the concentration-time curve, 6 mg/mL/min). Both groups received trastuzumab (6 mg/kg; loading dose 8 mg/kg) and pertuzumab (420 mg intravenously; loading dose 840 mg) every 3 weeks. Main Outcomes and Measures Three-year EFS, OS, and safety. Results A total of 438 women were randomized, with 219 per group (anthracycline group, median age, 49 years [interquartile range, 43-55 years]; and nonanthracycline group, median age, 48 years [interquartile range, 43-56 years]). A total of 23 EFS events (10.5%) occurred in the anthracycline group and 21 EFS events (9.6%) occurred in the nonanthracycline group (hazard ratio, 0.90; 95% CI, 0.50-1.63; favoring nonanthracyclines). Three-year EFS estimates were 92.7% (95% CI, 89.3%-96.2%) in the anthracycline group and 93.6% (95% CI, 90.4%-96.9%) in the nonanthracycline group and 3-year OS estimates were 97.7% (95% CI, 95.7%-99.7%) in the anthracycline group and 98.2% (95% CI, 96.4%-100%) in the nonanthracycline group. The results were irrespective of hormone receptor and nodal status. A decline in left ventricular ejection fraction of 10% or more from baseline to less than 50% was more common in patients who received anthracyclines than those who did not (17 of 220 [7.7%] vs 7 of 218 [3.2%];P = .04). Two patients treated with anthracyclines developed acute leukemia. Conclusions and Relevance This follow-up analysis of the TRAIN-2 study shows similar 3-year EFS and OS estimates with or without anthracyclines in patients with stage II and IIIERBB2-positive breast cancer. Anthracycline use is associated with increased risk of febrile neutropenia, cardiotoxic effects, and secondary malignant neoplasms. Trial Registration ClinicalTrials.gov Identifier:NCT01996267

Dose redistribution, where radio-resistant parts of the tumour are boosted while the border of the planning target volume receives a lower dose has the potential to increase local control in advanced head and neck squamous cell carcinoma (HNSCC). In this treatment planning study for 20 patients, standard radiotherapy (RT) of 70 Gy, was compared to redistributed RT following the ARTFORCE trial protocol (NCT01504815), i.e., a fluorodeoxyglucose-positron emission tomography (FDG-PET) based heterogeneous simultaneous-integrated-boost to a total dose of 64–84 Gy. Redistribution marginally increased the mean ipsilateral ⧹contralateral parotid dose by 1.55⧹0.55 Gy but not dose to other organs at risk. Keywords: Head and neck cancer, Radiotherapy, Dose-painting, Treatment planning

Background The discovery of novel biomarkers that predict treatment response in advanced cancer patients requires acquisition of high-quality tumor samples. As cancer evolves over time, tissue is ideally obtained before the start of each treatment. Preferably, samples are freshly frozen to allow analysis by next-generation DNA/RNA sequencing (NGS) but also for making other emerging systematic techniques such as proteomics and metabolomics possible. Here, we describe the first 469 image-guided biopsies collected in a large collaboration in The Netherlands (Center for Personalized Cancer Treatment) and show the utility of these specimens for NGS analysis. Patients and Methods Image-guided tumor biopsies were performed in advanced cancer patients. Samples were fresh frozen, vital tumor cellularity was estimated, and DNA was isolated after macrodissection of tumor-rich areas. Safety of the image-guided biopsy procedures was assessed by reporting of serious adverse events within 14 days after the biopsy procedure. Results Biopsy procedures were generally well tolerated. Major complications occurred in 2.1%, most frequently consisting of pain. In 7.3% of the percutaneous lung biopsies, pneumothorax requiring drainage occurred. The majority of samples (81%) contained a vital tumor percentage of at least 30%, from which at least 500 ng DNA could be isolated in 91%. Given our preset criteria, 74% of samples were of sufficient quality for biomarker discovery. The NGS results in this cohort were in line with those in other groups. Conclusion Image-guided biopsy procedures for biomarker discovery to enable personalized cancer treatment are safe and feasible and yield a highly valuable biobank.

Objectives To guide decision making in preventing over- or under-treatment in older breast cancer patients who have undergone breast conserving surgery, we analyzed prognostic factors and risk of recurrence in a consecutive series of patients ≥ 65 years old with breast cancer and identified subgroups that may benefit or not from more intensive treatment. Methods Patients ≥65 years of age with breast cancer (pT1-2/pN0-2) treated with breast conserving surgery and postoperative radiation therapy at the Netherlands Cancer Institute (NKI) between 1980 and 2008 were identified. Endpoints were locoregional recurrence (LRR), distant metastasis (DM) and overall survival (OS). Multivariable analyses were performed using Cox proportional hazards models. Results 1922 patients with a median age of 70 years were analyzed. The 5- and 10- years LRR rates were 2% and 3% respectively. In multivariable analysis there was no significant factor influencing LRR risk. Patients with low risk tumors (node negative patients with T1 and ER positive, grade 1 or 2) had lower risk of DM (HR 0.26) and better OS (HR 0.65) compared to patients with higher risk tumors (grade 3 and/or node positive). Conclusion In elderly breast cancer patients the risk of LRR and DM is low. In patients with less favorable characteristics the risk of LRR is equally low, with a higher risk to develop DM and worse OS. Treatment in the low risk group may be minimized, while for the higher risk group adjuvant treatment could be intensified.

Background: Optimal follow-up (FU) strategy to detect potentially curable (PC) recurrences after treatment of localised clear cell renal cell carcinoma (ccRCC) is unclear. This study retrospectively analysed a large international database to determine recurrence patterns and overall survival (OS), as part of a wider project to issue recommendations on FU protocols. Objective: To analyse associations between RCC recurrences in patients with ccRCC, their risk group stratifications, treatments, and subsequent outcomes. Design, setting, and participants: Nonmetastatic ccRCC patients treated with curative intent between 1 January 2006 and 31 December 2011, with at least 4 yr of FU, were included. Patient, tumour and recurrence characteristics, Leibovich score, and management and survival data were recorded. Isolated local, solitary, and oligometastatic (three or fewer lesions at a single site) recurrences were considered PC, while all others were probably incurable (PI). Intervention: Primarily curative surgical treatment of ccRCC while at recurrence detection metastasectomy, systemic therapy, best supportive care, or observation. Outcome measurements and statistical analysis: Incidence, time to recurrence (TTR), and OS were measured. Competing risk analysis, Kaplan-Meier, and Cox regression models were used. Results and limitation: Of 1265 patients with ccRCC, 286 had a recurrence, with 131 being PC and 155 PI. Five-year cumulative risks of recurrence for low- (n = 53), intermediate- (n = 105), and high-risk (n = 128) patients were, respectively, 7.2%, 23.2%, and 61.6%, of whom 52.8%, 37.1%, and 30.5% were PC, respectively. Median TTR was 25.0 for PC patients versus 17.3 mo for PI patients (p = 0.004). Median OS was longer in PC compared with that in PI patients (p< 0.001). Competing risk analysis showed highest risk of ccRCC-related death in younger and high-risk patients. Limitations were no data on comorbidities, retrospective cohort, and insufficient data excluding 12% of cohort. Conclusions: Low-risk group recurrences are rare and develop later. Treatment of recurrences with curative intent is disappointing, especially in high-risk patients. An age- and risk score-dependent FU approach is suggested. Patient summary: We analysed data from eight European countries, and found that the incidence of the kidney cancer recurrence and patient survival correlated with clinical factors known to predict cancer recurrence reliably and age. We conclude that these factors should be used to design follow-up strategies. Renal cell carcinoma recurrences are rare in low-risk patients. Potentially curable recurrences are more frequent in high-risk patients, but local treatment is unlikely to be curative. Competing risk analyses suggest age and risk score as important factors in developing follow-up strategies.

Presence of lymph node metastases (LNM) is an important prognostic factor for cancer-specific survival (CSS) in patients with upper tract urothelial carcinoma (UTUC). In various neoplasms,To determine the diagnostic value of FDG-PET/CT for LN staging in patients with UTUC.Data of 152 patients with UTUC who underwent FDG-PET/CT followed by surgical treatment in eight centers between 2007 and 2017 were retrospectively collected. Patients receiving neoadjuvant chemotherapy were excluded.FDG-PET/CT results were compared with histopathology after lymph node dissection (LND). Recurrence-free survival (RFS), CSS, and overall survival (OS) were analyzed using Kaplan-Meier estimates, and compared for patients with and without suspicious LNs on FDG-PET/CT.We included 117 patients, of whom 62 underwent LND. Seventeen patients had LNM at histopathological evaluation. Sensitivity and specificity of FDG-PET/CT for diagnosis of LNM were 82% (95% confidence interval [CI]: 57-96) and 84% (95% CI: 71-94), respectively. RFS was significantly worse in patients with LN-positive FDG-PET/CT than in those with LN-negative FDG-PET/CT (p=0.03). CSS (p=0.11) and OS (p=0.5) were similar between groups. This study is limited by its retrospective design and by its sample size. Our results warrant further validation.FDG-PET/CT has 82% sensitivity and 84% specificity for the detection of LNM in patients with UTUC. Presence of suspicious LNs on FDG-PET/CT is associated with worse RFS.In patients with upper tract urothelial cancer, positron emission tomography with computed tomography (PET/CT) scans can detect lymph node metastases with noteworthy accuracy. Presence of suspicious lymph nodes on

To investigate associations of early post-treatmentForty-seven stage IIIA-B NSCLC-patients included in a randomized phase II-trial (NTR2230) received 66 Gy (24x2.75 Gy) with low dose Cisplatin +/- Cetuximab. FDG-PET-scans were performed at baseline and 4 weeks post-treatment (range, 1.6-10.1). SUVMetrics resulted from the post-treatment scan and relative response were associated with outcome, but baseline metrics were not. Primary tumor metrics were stronger associated with all outcomes than lymph node metrics. Both the volumetric (TLG/MTV) and intensity (SUVEarly post-treatment PET-metrics are associated with treatment outcome in LA-NSCLC patients treated with chemoradiotherapy. Both volumetric and intensity PET-metrics are useful, but more for the primary tumor than for lymph nodes.

There is a clear and unmet clinical need for biomarkers to predict responsiveness to chemotherapy for cancer. We developed an in vitro test based on patient-derived tumor organoids (PDOs) from metastatic lesions to identify nonresponders to standard-of-care chemotherapy in colorectal cancer (CRC). In a prospective clinical study, we show the feasibility of generating and testing PDOs for evaluation of sensitivity to chemotherapy. Our PDO test predicted response of the biopsied lesion in more than 80% of patients treated with irinotecan-based therapies without misclassifying patients who would have benefited from treatment. This correlation was specific to irinotecan-based chemotherapy, however, and the PDOs failed to predict outcome for treatment with 5-fluorouracil plus oxaliplatin. Our data suggest that PDOs could be used to prevent cancer patients from undergoing ineffective irinotecan-based chemotherapy.

Highlights • SBRT for liver metastases is a safe alternative for surgical resection or ablation. • High dose (>100 Gy) SBRT provides better local control than low dose (≤100 Gy) SBRT. • Toxicity rates of SBRT are low and do not increase after dose escalation. • Dose escalation is positively associated with overall survival., Introduction Stereotactic Body Radiation Therapy (SBRT) is a treatment option for patients with liver metastases. This study evaluated the impact of high versus low dose image-guided SBRT of hepatic metastases. Methods and materials This is a single-center retrospective study of patients with liver metastases treated with SBRT. For analyses, patients were divided into two groups: ≤100 Gy and >100 Gy near-minimum Biological Effective Doses (BED98%). The main outcomes were local control (LC), toxicity and overall survival (OS). Cox regression analyses were performed to determine prognostic variables on LC and OS. Results Ninety patients with 97 liver metastases (77% colorectal) were included. Median follow-up was 28.6 months. The two-year LC rates in the ≤100 Gy and >100 Gy BED98% group were 60% (CI: 41–80%) and 90% (CI: 80–100%), respectively (p = 0.004). Grade 3 toxicity occurred in 7% vs 2% in the ≤100 Gy and >100 Gy group (p = 0.23). Two-year OS rates in the ≤100 Gy and >100 Gy group were 48% (CI: 32–65%) and 85% (CI: 73–97%), respectively (p = 0.007). In multivariable Cox regression analyses, group dose and tumor volume were significantly correlated with LC (HR: 3.61; p = 0.017 and HR: 1.01; p = 0.005) and OS (HR: 2.38; p = 0.005 and HR: 1.01; p =

Objective: Modality and frequency of image-based renal cell carcinoma (R.C.C.) follow-up strategies are based on risk of recurrence. Using the R.E.C.U.R.-database, frequency of imaging was studied in regard to prognostic risk groups. Furthermore, it was investigated whether imaging modality utilized in contemporary follow-up were associated with outcome after detection of recurrence. Moreover, outcome was compared based on whether the assessment of potential curability was a pre-defined set of criteria’s (per-protocol) or stated by the investigator. Materials and methods: Consecutive non-metastatic R.C.C. patients (n = 1,612) treated with curative intent at 12 institutes across eight European countries between 2006 and 2011 were included. Leibovich or U.I.S.S. risk group, recurrence characteristics, imaging modality, frequency and survival were recorded. Primary endpoints were overall survival (O.S.) after detection of recurrence and frequency of features associated with favourable outcome (non-symptomatic recurrences and detection within the follow-up-programme). Results: Recurrence occurred in 336 patients. Within low, intermediate and high risk for recurrence groups, the frequency of follow-up imaging was highest in the early phase of follow-up and decreased significantly over time (p < 0.001). However, neither the image modality for detection nor ≥ 50% cross-sectional imaging during follow-up were associated with improved O.S. after recurrence. Differences between per protocol and investigator based assessment of curability did not translate into differences in O.S. Conclusions: As expected, the frequency of imaging was highest during early follow-up. Cross-sectional imaging use for detection of recurrences following surgery for localized R.C.C. did not improve O.S. post-recurrence. Prospective studies are needed to determine the value of imaging in follow-up.