Background: Male breast cancer (MBC) is very rare and has worse outcome compared to BC in women. MBC specific interventions are lacking. Non-adherence to mainstay tamoxifen treatment is common, due to feminizing side effects and reduced quality of life, and related to worse survival. Thus, well-tolerated endocrine treatment is an unmet need in MBC. MBC expresses both estrogen- and androgen receptors (ER and AR) in 97% of cases. As the AR functions as tumor suppressor in ER+ BC, adding testosterone to tamoxifen may improve both tumor response and tolerability in MBC. Therefore, we assessed the safety profile of tamoxifen plus testosterone in patients with metastatic MBC. Methods: In this single-arm pilot study, patients received tamoxifen 20mg plus testosterone 25mg once a day, increased to 50mg after 3 weeks in case of good tolerance. Primary endpoint was safety (assessed as grade 3-4 adverse events (AEs) according to Common Terminology Criteria of Adverse Events (CTCAE) v5.0). Secondary endpoint was tumor response and duration (according to RECIST1.1) assessed after 8 weeks, thereafter every 12 weeks. Results: Five MBC patients were enrolled with median age of 63 years, and mean two (1-3) previous endocrine treatment lines for metastatic MBC. All patients had received prior tamoxifen monotherapy, in either adjuvant or metastatic setting. No grade 3-4 AEs were observed. Two out of 19 grade 1-2 AEs were possibly related to the treatment: grade 1 anxiety and nausea, both spontaneously resolved. Other low grade AEs were probably related to (progressive) disease (n=7) or from another cause not likely related to the treatment (n=10). Regarding responses, 3/5 patients showed clinical benefit with in one patient a partial response duration of 10 months and in two patients ongoing stable disease at the time of analysis (resp. 12 and 15 months), 2/5 patients had progressive disease at 8 weeks. All patients spontaneously reported improved well-being. Conclusions: In this unique MBC intervention trial, tamoxifen plus testosterone showed good safety, tolerability as well as long-term responses in the majority of patients. Therefore, this could be a promising new endocrine approach in this rare MBC population. Citation Format: Jasmine Moustaquim, Jasper van Geel, Michel van Kruchten, Erik de Vries, Marcel Stokkel, Andor Glaudemans, Geke Hospers, Carolien Schröder. Testosterone & Tamoxifen (T&T) trial: adding Testosterone to Tamoxifen in male breast cancer patients [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-10-01.

PURPOSE:Intensity modulated radiation therapy (IMRT) aims to lower radiation-related toxicity by delivering more conformal radiation therapy compared with 3-dimensional conformal radiation therapy (3D-CRT). This study investigated whether IMRT (including volumetric modulated arc therapy) resulted in less acute and late radiation-related toxicity and better treatment compliance compared with 3D-CRT in the phase 3 RAPIDO trial. METHODS AND MATERIALS:Patients with locally advanced rectal cancer (LARC), treated with short-course radiation therapy followed by consolidation therapy (total neoadjuvant treatment [TNT] arm) or chemoradiation therapy with optional postoperative chemotherapy (CRT arm) were included. IMRT was compared with 3D-CRT, stratified by treatment arm. Acute, late, and persistent toxicity endpoints included radiation-related gastrointestinal, general, genitourinary, hematologic, and sexual adverse events (CTCAEv4). Toxicity endpoints were analyzed as binary outcomes (grade ≥ 1 vs grade 0 and grade ≥ 3 vs grade 0-2) with univariable and multivariable logistic regression analyses. RESULTS:For acute and late toxicity analyses, 460 and 352 patients were eligible in the TNT arm, respectively, and 441 and 321 patients in the CRT arm. IMRT was delivered in 29% of the patients. After IMRT in the TNT arm, more acute fatigue grade ≥ 1 (OR, 2.71; 95% CI, 1.60-4.60; P < .001) and more acute nausea/vomiting grade ≥1 (OR, 1.79; 95% CI, 1.15-2.79; P = .010) was observed compared with 3D-CRT. After IMRT in the CRT arm, more any late radiation-related toxicity grade ≥ 1 (OR, 2.14; 95% CI, 1.28-3.57; P = .004) and more late sexual toxicity grade ≥ 1 (OR, 2.31; 95% CI, 1.24-4.29; P = .008) was observed compared with 3D-CRT. No differences were found for other grade ≥ 1 toxicity endpoints, grade ≥ 3 toxicity, or treatment compliance. Persistent toxicity was rare in both groups. CONCLUSIONS:IMRT was not associated with less radiation-related toxicity compared with 3D-CRT after TNT or CRT. In contrast, some lower grade toxicities were more frequent after IMRT, in particular fatigue during TNT. Late persistent toxicity was uncommon in both groups.

Background A decision model for patients with advanced melanoma to estimate outcomes of a wide range of treatment sequences is lacking. Objectives To develop a decision model for advanced melanoma to estimate outcomes of treatment sequences in clinical practice with the aim of supporting decision making. The article focuses on methodology and long-term health benefits. Methods A semi-Markov model with a lifetime horizon was developed. Transitions describing disease progression, time to next treatment, and mortality were estimated from real-world data (RWD) as a function of time since starting treatment or disease progression and patient characteristics. Transitions were estimated separately for melanoma with and without a BRAF mutation and for patients with favorable and intermediate prognostic factors. All transitions can be adjusted using relative effectiveness of treatments derived from a network meta-analysis of randomized controlled trials (RCTs). The duration of treatment effect can be adjusted to obtain outcomes under different assumptions. Results The model distinguishes 3 lines of systemic treatment for melanoma with a BRAF mutation and 2 lines of systemic treatment for melanoma without a BRAF mutation. Life expectancy ranged from 7.8 to 12.0 years in patients with favorable prognostic factors and from 5.1 to 8.7 years in patients with intermediate prognostic factors when treated with sequences consisting of targeted therapies and immunotherapies. Scenario analyses illustrate how estimates of life expectancy depend on the duration of treatment effect. Conclusion The model is flexible because it can accommodate different treatments and treatment sequences, and the duration of treatment effects and the transitions influenced by treatment can be adjusted. We show how using RWD and data from RCTs can harness advantages of both data sources, guiding the development of future decision models. Highlights The model is flexible because it can accommodate different treatments and treatment sequences, and the duration of treatment effects as well as the transitions that are influenced by treatment can be adjusted. The long-term health benefits of treatment sequences depend on the place of different therapies within a treatment sequence. Assumptions about the duration of relative treatment effects influence the estimates of long-term health benefits. We show how the use of real-world data and data from randomized controlled trials harness the advantages of both data sources, guiding the development of future decision models.

Background This study aims to evaluate the cost-effectiveness of treatment sequences for patients with advanced melanoma with a BRAF mutation in the Netherlands from a societal perspective. Methods A semi-Markov model with a life-time horizon has been used to evaluate cost-effectiveness of 21 treatment sequences. Real-world data from the Dutch Melanoma Treatment Registry (DMTR) were used to estimate time to progression, next treatment and death. Utilities by health state as well as hospital costs, health care costs outside the hospital, patient and family costs and productivity costs were also derived from the DMTR. Drug costs were estimated based on the recommended dose and duration of treatment. Incremental cost-effectiveness ratios (ICERs) were presented as incremental costs per QALY gained. Results Health benefits of treatment sequences consisting of targeted therapies and immunotherapies vary between 2.3 and 5.8 QALYs gained per patient when compared to chemotherapy. The increase in costs varies between €112,000 and €383,000. The efficiency frontier consists of nivolumab in the first line followed by ipilimumab in the second line (ICERs of €42,000/QALY and €44,000/QALY), nivolumab in the first line followed by encorafenib plus binimetinib in the second line (ICERs of €71,000/QALY and €68,000/QALY) and nivolumab plus ipilimumab in the first line followed by encorafenib plus binimetinib in the second line (ICERs of €74,000/QALY and €76,000/QALY). The first treatment given within a sequence as well as assumptions regarding treatment duration have a substantial impact on cost-effectiveness outcomes. Conclusion The ICERs can be considered cost-effective at different cost-effectiveness thresholds.

9541 Background: Biomarkers to predict response to immune checkpoint inhibition (ICI)-treated melanoma are limited. This study evaluates AI-detected tumor-infiltrating lymphocytes (TILs) on pretreatment metastatic pathology specimens as a biomarker for response and survival in ICI-treated patients. Methods: Patients treated with first-line anti-PD1 ± anti-CTLA4 for advanced melanoma were retrospectively identified from 11 Dutch melanoma centers. Pre-treatment TILs were quantified on H&E stained slides using the Hover-NeXt algorithm trained on an independent melanoma dataset with 166.718 pathologist checked manually annotated cells. The average percentage of TILs per 200 µm² tumor area was calculated. The primary outcome was response to ICI per RECIST 1.1 with overall survival (OS) and progression free survival (PFS) as secondary outcomes. Univariable and multivariable logistic and Cox regression analyses assessed associations between a 10% increase in TILs present in pre-treatment metastatic slides and clinical outcomes. Multivariable analyses were adjusted for age, sex, disease stage, BRAF mutation, LDH and performance score. Objective response rate and Kaplan Meier survival analysis were stratified by TIL tertiles. Results: Metastatic melanoma specimens were available for 1246 patients, 441 received anti-PD1 + anti-CTLA4. Median TIL percentage was 10.2% (interquartile range 5.5% – 17.2%). A 10% higher baseline TIL percentage was associated with response (adjusted OR 1.39 [95% 1.21-1.58]), PFS (adjusted HR 0.87 [95% CI 0.81 – 0.94]) and OS (adjusted HR 0.84 [95% CI 0.77 – 0.93] in univariable and multivariable analysis (Table 1). Stratified analysis showed significant associations between TILs, response, and survival in both anti-PD1 monotherapy and combination therapy. Conclusions: AI-quantified TILs in pre-treatment melanoma metastases are correlated with improved response rates and survival in ICI treated patients. This correlation is independent of known clinical predictors. Outcome ICI Lowest Tertile Middle Tertile Highest Tertile Univariable OR / HR [95% CI] Multivariable OR / HR [95% CI] Response (%) All 47.9% 57.8% 64.5% 1.35 [1.21 – 1.52] 1.39 [1.21 – 1.58] Anti-PD1 45.2% 57.1% 66.7% 1.42 [1.24 – 1.64] 1.37 [1.17 – 1.60] Anti-PD1 + Anti-CTLA4 51.4% 62.2% 58.7% 1.23 [1.00 – 1.53] 1.48 [1.13 – 1.94] PFS (months) All 5.4 9.7 15.3 0.87 [0.81 – 0.93] 0.87 [0.81 – 0.94] Anti-PD1 5.4 11.8 16.5 0.85 [0.79 – 0.92] 0.89 [0.81 – 0.97] Anti-PD1 + Anti-CTLA4 5.3 11.0 10.2 0.89 [0.78 – 1.02] 0.80 [0.69 – 0.94] OS (months) All 21.4 38.4 49.2 0.81 [0.75 – 0.88] 0.84 [0.77 – 0.93] Anti-PD1 21.1 36.5 51.4 0.79 [0.71 – 0.87] 0.86 [0.77 – 0.96] Anti-PD1 + Anti-CTLA4 21.4 77.8 46.4 0.88 [0.75 – 1.03] 0.82 [0.69 – 0.97]

Background The association of body composition with checkpoint inhibitor outcomes in melanoma is a matter of ongoing debate. In this study, we aim to investigate body mass index (BMI) alongside computed tomography (CT)-derived body composition metrics in the largest cohort to date.Methods Patients treated with first-line anti-PD1 +/- anti-CTLA4 for advanced melanoma were retrospectively identified from 11 melanoma centers in The Netherlands. From baseline CT scans, 5 body composition metrics were extracted: subcutaneous adipose tissue index, visceral adipose tissue index, skeletal muscle index, density, and gauge. These metrics were correlated in univariable and multivariable Cox proportional hazards analysis with progression-free survival, overall survival, and melanoma-specific survival (PFS, OS, and MSS).Results A total of 1471 eligible patients were included. Median PFS and OS were 9.1 and 38.1 months, respectively. Worse PFS was observed in underweight patients (multivariable hazard ratio [HR] = 1.86, 95% CI = 1.14 to 3.06). Furthermore, prolonged OS was observed in patients with higher skeletal muscle density (multivariable HR = 0.88, 95% CI = 0.81 to 0.97) and gauge (multivariable HR = 0.61, 95% CI = 0.82 to 0.998), whereas higher visceral adipose tissue index was associated with worse OS (multivariable HR = 1.12, 95% CI = 1.04 to 1.22). No association with survival outcomes was found for overweight, obesity, or subcutaneous adipose tissue.Conclusion Our findings suggest that underweight BMI is associated with worse PFS, whereas higher skeletal muscle density and lower visceral adipose tissue index were associated with improved OS. These associations were independent of known prognostic factors, including sex, age, performance status, and extent of disease. No significant association between higher BMI and survival outcomes was observed.

Intrapatient heterogeneity of estrogen receptor (ER) expression on 16α-[18F]fluoro-17β-estradiol ([18F]FES) PET is related to outcome in patients with ER-positive metastatic breast cancer (MBC), but a validated and practical method to support clinical decision-making is lacking. Therefore, the [18F]FES PET heterogeneity score (i.e., percentage of [18F]FES-positive metastases) was validated as a prognostic factor for endocrine therapy response and survival in a large cohort of patients with newly diagnosed MBC. Furthermore, we explored 2 less laborious methods to predict the [18F]FES PET heterogeneity score. Methods: Patients with ER-positive MBC included in the IMPACT-MBC study, who received baseline [18F]FES and [18F]FDG PET and first-line endocrine therapy, were included in this subanalysis. ER homogeneous (100% [18F]FES-positive lesions) and ER heterogeneous (both [18F]FES-positive and [18F]FES-negative lesions) MBC was distinguished by manual segmentation of all lesions on [18F]FES PET and related to progression-free survival (PFS) and overall survival (OS). In addition, the positive predictive value of the visual assessment and the 5-largest-lesions assessment to predict homogeneous MBC in all lesions on [18F]FES PET was determined. Results: From the 102 MBC patients eligible for the present retrospective subanalysis, 46 had ER homogeneous MBC and 56 had ER heterogeneous MBC. Differences were found between ER homogeneous and ER heterogeneous MBC for median PFS (19.8 vs. 15.0 mo; hazard ratio, 0.63; 95% CI, 0.41-0.96; P = 0.03) and median OS (62.5 vs. 34.7 mo; hazard ratio, 0.65; 95% CI, 0.38-1.08; P = 0.09). Twenty-one (38%) of 61 patients with ER homogeneous MBC by visual analysis and 37 (45%) of 83 patients with ER homogeneous MBC by the 5-largest-lesions method had ER heterogeneous MBC by manual segmentation of all lesions on [18F]FES PET (positive predictive value, 0.66 and 0.55, respectively). Conclusion: Patients with ER-positive homogeneous MBC showed a trend toward superior PFS and OS compared with patients with ER heterogeneous MBC. This analysis confirmed and validated the prognostic value of the [18F]FES PET heterogeneity score for endocrine therapy response and survival in a large cohort of MBC patients. The less laborious visual and 5-largest-lesions methods were inferior compared with assessment based on the [18F]FES PET heterogeneity score in all lesions.

Owing to insufficient evidence, tumor budding (TB) is not currently evaluated in colorectal cancer (CRC) biopsies. This study investigates TB in CRC by establishing the value of intratumoral budding (ITB) in resection specimens and assessing the feasibility and clinical value of TB in biopsies. TB was assessed using an algorithm in all cases. In a test cohort of 555 primarily surgically treated CRC patients, we assessed the prognostic impact of ITB compared with peritumoral budding (PTB). The distribution of ITB in the uppermost 5 mm of resection specimens was analyzed to validate TB counting in biopsies. We further validated the prognostic and predictive impact of TB in biopsies of 285 rectal cancer patients, focusing on overall survival and response to neoadjuvant therapy. Highgrade TB, whether intratumoral or peritumoral and in biopsies or resections, was associated with advanced pathological stage, lymphatic invasion, infiltrative tumor border, and poor overall survival in the test cohort. Superficial ITBs (0-3 mm from the lumen) accurately predicted the final TB grade based on PTB in 87% of tumors, with 87% of tumors having at least 1 superficial ITB hotspot. ITB (hazard ratio, 3.5; 95% CI, 1.1-10.8) was an independent predictor of overall survival, unlike PTB. In the validation cohort, TB presence in biopsies significantly reduced the likelihood of achieving a pathological complete response (odds ratio, 0.3; 95% CI, 0.1-0.7; P 1/4 .007). ITB is as prognostic as PTB, and evaluating both can improve risk stratification in CRC. TB assessment in biopsies can identify poor prognosis and predict response to neoadjuvant therapy. (c) 2024 THE AUTHORS. Published by Elsevier Inc. on behalf of the United States & Canadian Academy of Pathology. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).

Importance:Easy and accessible biomarkers associated with response to immune checkpoint inhibition (ICI)-treated melanoma are limited. Objective:To evaluate artificial intelligence (AI)-detected tumor-infiltrating lymphocytes (TILs) on pretreatment melanoma metastases as a biomarker for response and survival in patients treated with ICIs. Design, Setting, and Participants:This multicenter cohort study included patients with advanced melanoma treated with first-line anti-programmed cell death 1 protein (PD-1) with or without anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) between January 2016 and January 2023 at 11 melanoma treatment centers in the Netherlands. Data were analyzed from January to July 2025. Exposure:All patients received first-line anti-PD-1 with or without anti-CTLA-4. Main Outcomes and Measures:The percentage of TILs inside manually annotated tumor area in hematoxylin-eosin-stained pretreatment metastases was determined using the Hover-NeXt model trained and evaluated on an independent melanoma dataset containing 161 835 pathologist-verified manually annotated cells. The primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS). Correlation with manual TILs, scored according to the guidelines stated by the Immuno-Oncology Biomarkers Working Group, was evaluated with Spearman correlation coefficients. Logistic regression and Cox proportional regression were conducted, adjusted for age, sex, disease stage, ICI type, BRAF status, brain metastases, lactate dehydrogenase level, and performance status. Results:Of 1202 included patients with advanced cutaneous melanoma, 445 (37.0%) were female and 757 (63.0%) were male, and the median (IQR) age was 67.0 (57.0-74.0) years. The median follow-up was 36.3 months (95% CI, 34.0-39.1). Metastatic melanoma specimens were available for 1202 patients, of whom 423 received combination therapy. The median (range) TIL percentage was 9.9% (0.3%-69.4%). A 10% increase in TILs was associated with increased ORR (adjusted odds ratio, 1.40; 95% CI, 1.23-1.59), PFS (adjusted hazard ratio, 0.85; 95% CI, 0.79-0.92), and OS (adjusted hazard ratio, 0.83; 95% CI, 0.76-0.91). Results were consistent for both patients treated with anti-PD-1 monotherapy and patients treated with combination treatment with anti-PD-1 plus anti-CTLA-4. When comparing manual TIL scoring with AI-detected TILs, associations with response and survival were consistently stronger for AI-detected TILs. Conclusions and Relevance:In this cohort study, among patients with advanced melanoma, higher levels of AI-detected TILs on pretreatment hematoxylin-eosin slides were independently associated with improved ICI response and survival. Given the accessibility of TIL scoring on routine histology, TILs may serve as a biomarker for ICI outcomes. To facilitate broader validation, the Hover-NeXt architecture and model weights are publicly available.

9573 Background: Adjuvant BRAF/MEK inhibitors (BRAF/MEKi) and immunotherapy with anti-PD-1 have become the standard of care for resected high-risk stage III and IV melanoma, but a head-to-head comparison is lacking. In our earlier study, we compared adjuvant BRAF/MEKi and anti-PD-1 in a nationwide cohort in the Netherlands. However, the follow-up was too limited for overall survival (OS) analysis. We present an updated analysis including OS with extended follow-up. Methods: We included all resected high-risk stage III melanoma patients treated with first-line adjuvant BRAF/MEKi and anti-PD-1 from the Dutch Melanoma Treatment Registry from 2018-2023. We performed a propensity score matched outcome analysis of 1- and 2-year recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and OS. Grade ≥ 3 toxicity rates and discontinuation rates due to toxicity were described. Results: In total, 225 BRAF/MEKi-treated patients and 729 anti-PD-1-treated patients were included. BRAF/MEKi-treated patients had lower disease stages (16.4% versus 10.2% stage IIIA disease; p=0.01) and more comorbidities (76.0% versus 63.8%; p<0.01) than anti-PD-1-treated patients. Median follow-up duration was 20.9 months. Two similar groups of 213 patients each were created by propensity score matching. Before matching, RFS and DMFS were significantly shorter in the anti-PD-1 treated patients, OS was not (Table). After matching, the 1- and 2-year RFS, DMFS and OS rates were not significantly different (Table). Toxicity data will be presented at the meeting. Conclusions: Our results suggest no significant differences in outcomes between adjuvant BRAF/MEKi and anti-PD-1 treatment in stage III melanoma.[Table: see text]

BACKGROUND: Detection of invasive lobular carcinoma (ILC) with standard imaging modalities can be challenging. [18F]fluorodeoxyglucose (FDG) PET is commonly used in the work up of first presentation of metastatic breast cancer (MBC), but may be suboptimal for ILC due to lower metabolic activity compared to invasive ductal cancer. Imaging with [18F]fluoro-17b-estradiol (FES) PET measures whole-body estrogen receptor (ER) expression, which is generally high in ILC. Whether FES-PET outperforms FDG-PET in detecting metastatic ILC (mILC) lesions -and should therefore be the first-step imaging modality for mILC work up- remains unclear. Therefore, we compared the sensitivity of FDG- and FES-PET to detect ILC metastases, in patients who were enrolled in the prospective IMPACT-MBC study. METHODS: In IMPACT-MBC (NCT01957332), 200 patients with newly diagnosed MBC underwent baseline FDG-PET, FES-PET, computed tomography (CT) scan and bone scintigraphy in addition to a metastasis biopsy. In this subanalysis, patients with ER+ mILC were included. Metastases were visually identified on FDG- and FES-PET and expressed as the total number and percentage of all metastases detected on all imaging modalities together. Results were analyzed on patient and lesion level. RESULTS: Twenty-six patients with ER+ ILC were included, with a median age of 57 years. Mean number of detected metastases per patient was 34 (range 2-77) with FDG-PET and 33 (range 0-88) with FES-PET. In 12 patients (46%), FES-PET detected more metastases than FDG-PET, whereas FDG-PET detected more metastases than FES-PET in another 12 patients (46%), and in two patients (8%) the same number of metastases was detected with both scans. In total, 1101 metastases were detected with all imaging modalities. A total of 853 metastases were detected with FDG-PET and 859 metastases were detected with FES-PET. This results in a sensitivity of 77.5% (95% CI 75 – 80) for FDG-PET and 78% (95% CI 76 – 80) for FES-PET. CONCLUSIONS: This is the largest prospective cohort comparing FDG-PET with FES-PET for baseline work up in mILC. FES-PET does not outperform FDG-PET in detecting ILC metastases, and the two techniques have similar sensitivity on a group level. For clinical practice, in light of wider availability of FDG-PET and detection of equal or more ILC metastases in the majority of patients, FDG-PET remains the first-step imaging modality for mILC. However, in a considerable part of patients with mILC, FES-PET detects more ILC metastases than FDG-PET. Therefore, in case of persistent clinical dilemmas or doubts, an additional FES-PET should certainly be considered in mILC. Citation Format: Jasmine Moustaquim, Gabriëlle E. van Wonderen, Jasper J. L. van Geel, Michel van Kruchten, Erik F.J. de Vries, Agnes Jager, Evelien Kuip, Marcel P. M. Stokkel, Andor W.J.M. Glaudemans, Geke A. P. Hospers, C. Willemien Menke van der Houven van Oordt, Bert van der Vegt, Elisabeth G.E. de Vries, Carolina P. Schröder. Comparative analysis of [18F]FES- and [18F]FDG-PET in patients with metastatic ER+ lobular breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS11-03.

BACKGROUND:Detection of metastatic invasive lobular carcinoma (mILC) with standard imaging is challenging. 2-[18F]Fluoro-2-deoxyglucose (FDG) PET/CT is commonly used in the work-up of metastatic breast cancer (MBC), but may be suboptimal for mILC. 16α-[18F]Fluoro-17β-estradiol (FES) PET/CT measures estrogen receptor (ER) expression, which is generally high in mILC. To assess whether FES-PET/CT outperforms FDG-PET/CT, we compared the detection rate of both scans to identify mILC, in patients who were enrolled in the prospective IMPACT-MBC study. METHODS:Patients with newly diagnosed ER-positive mILC underwent baseline FDG-PET/CT, FES-PET/CT, diagnostic computed tomography (CT), bone scintigraphy, and a biopsy of a metastasis. The number of metastases visible on FDG-PET/CT or FES-PET/CT was compared to all metastases identified with any imaging modality. Results were analyzed at patient and lesion level. RESULTS:Twenty-six out of 200 patients had ER-positive mILC and were included in this sub-analysis. Mean number of metastases per patient was 34 (2-77) with FDG-PET/CT and 33 (0-88) with FES-PET/CT. In 12 patients (46 %), more metastases were visible on FDG-PET/CT than FES-PET/CT, in 12 patients, this was the reverse. Out of 1101 metastases detected with all imaging modalities, 889 metastases were detected with FDG-PET/CT and 859 with FES-PET/CT, resulting in a detection rate of 81 % (95 % CI 78 - 83) and 78 % (95 % CI 76 - 80), respectively. Two patients had a negative FES-PET/CT, while no patients had a negative FDG-PET/CT. CONCLUSIONS:FES-PET/CT and FDG-PET/CT have a similar detection rate in mILC, and FDG-PET/CT should be used for first-step imaging. However, as more metastases are visible on FES-PET/CT in a considerable part of mILC patients, in case of doubt, an additional FES-PET/CT should be considered.

BACKGROUND:Perineal wound complications (PWCs) occur in 15-30% of patients after abdominoperineal excision (APE) and are associated with adverse events, such as delayed wound healing, prolonged hospitalization, a delay in initiating postoperative chemotherapy, and decreased quality of life. Preoperative radiotherapy and chemotherapy are risk factors for wound complications. It is unknown whether total neoadjuvant treatment (TNT) affects the risk of PWCs compared with chemoradiotherapy (CRT). METHODS:This study compared patients from the experimental (EXP; short-course radiotherapy, chemotherapy, and surgery as TNT) and standard-of-care (STD; CRT, surgery, and postoperative chemotherapy depending on hospital policy) treatment arms of the RAPIDO trial who underwent APE within 6 months after preoperative treatment. The primary outcome was the incidence of PWCs (infection, abscess, dehiscence, wound discharge, presacral abscess affecting the perineum) of any grade ≤ 30 days after APE. Secondary outcomes were the incidence of PWCs >30 days after APE, length of hospital stay, characteristics associated with PWCs, and oncological outcomes in patients with versus without PWC. RESULTS:Of the 901 patients who started treatment (460 in EXP arm, 441 in STD arm), 153 (33%) and 160 (36%) underwent APE after TNT and CRT, respectively. After TNT and CRT, the incidence of PWCs ≤30 days after APE, readmission, and reoperation was 54 of 153 (35%) versus 53 of 160 (33%) (P = 0.69), 9% versus 12% (P = 0.54), and 7% versus 8% (P = 0.75), respectively. The median length of hospital stay was 2-3 days longer for patients with PWC. Univariable analysis revealed that pretreatment albumin <35 g/l, hypertension, and haemoglobin ≤ 8.0 mmol/l were associated with PWC. Oncological outcomes were similar between patients with and without PWCs. CONCLUSION:In the RAPIDO trial, TNT and CRT resulted in a similar incidence of PWCs among patients with high-risk locally advanced rectal cancer who underwent APE.

BACKGROUND:The Chemoradiotherapy for Oesophageal Cancer followed by Surgery Study (CROSS) regimen is currently offered to locally advanced esophageal cancer patients beyond the original eligibility criteria. This national population-based study assessed the safety in implementation regarding treatment outcome when extending these criteria. PATIENTS AND METHODS:Locally advanced esophageal cancer (cT1N+/T2-4aN0-3/M0) patients (n = 5061) from the Netherlands Cancer Registry treated according to the neoadjuvant chemoradiotherapy (nCRT) CROSS regimen between 2015 and 2022 were analyzed. A total of 1958 complied with the original criteria (O-CROSS group) and 1348 with one or more extended criteria (tumor length >8 cm, age >75 years, WHO score >2 and/or weight loss >10%) (E-CROSS group), eventually followed by resection in 1342 O-CROSS patients and 852 E-CROSS patients. Primary outcome was overall survival (OS), i.e. time interval from onset of nCRT (OS-nCRT) and from date of surgery (OS-surgery) until death or last follow-up. Secondary outcomes were disease-free survival, pathological complete response (pCR), surgical radicality, post-operative morbidity and mortality. Data were analyzed using the Kaplan-Meier method and Cox proportional hazards models. RESULTS:OS-nCRT was significantly lower in the E-CROSS compared with the O-CROSS (median of 30.3 months, 95% confidence interval 27.2-33.5 months versus 45.9 months, 95% CI 38.4-53.4 months, P < 0.001). Similarly, differences were observed in OS-surgery. When OS-nCRT and OS-surgery were adjusted for baseline covariates, however, no difference was found between both groups. Moreover, no differences were observed in disease-free survival, surgical radicality, and pCR. While not affecting post-operative mortality, significantly more anastomotic leakages and thromboembolic post-operative complications were seen in the O-CROSS group. CONCLUSION:Extending the CROSS criteria was associated with lower OS, which was caused by the higher age, weight loss >10% and WHO score in the E-CROSS group. The CROSS regimen can be used in a 'real-world' setting but individual factors that may contribute to OS should be considered in decision-making.

Background: Pathologic response following neoadjuvant immune checkpoint blockade (ICB) in stage III melanoma serves as a surrogate marker for long-term outcomes. This may support more personalized, responsedirected treatment strategies. Methods: The OpACIN-neo and PRADO trials were phase 2 studies evaluating neoadjuvant treatment with ipilimumab and nivolumab in stage III melanoma. In OpACIN-neo, all patients underwent therapeutic lymph node dissection (TLND) without subsequent adjuvant therapy. In contrast, PRADO explored a response- directed strategy, where patients achieving a major pathologic response (MPR) omitted TLND and adjuvant therapy, while those without a pathologic response (pNR) received TLND and adjuvant therapy. Here, we provide a descriptive post-hoc comparison of 3-year survival outcomes between the non-personalized approach in OpACINneo and the response-directed approach in PRADO. Results: For patients who achieved an MPR, the 3-year recurrence-free survival (RFS) was 93 % for those without TLND versus 96 % for those with TLND (log-rank p = 0.47), and distant metastasis-free survival (DMFS) was 98 % compared to 96 % (log-rank p = 0.49), respectively. For patients with pNR, 3-year RFS rates were 64 % for those receiving adjuvant systemic therapy and 35 % for patients without (log-rank p = 0.10). DMFS rates were Conclusions: These data suggest that TLND and adjuvant therapy may be safely omitted in most patients achieving an MPR, while adjuvant systemic therapy following TLND appears to improve RFS and DMFS in patients with pNR. Although these results are hypothesis-generating and require further validation, they offer a potential foundation for developing personalized neoadjuvant immunotherapy approaches.

[18F]FDG PET/CT plays a crucial role in evaluating cancer patients and assessing treatment response, including in BRAF-mutated melanoma. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) have emerged as promising alternatives to standardized uptake value (SUV)-based measures for tumor assessment. This study evaluates the predictive value of SUVpeak, MTV, and TLG in predicting progression-free survival (PFS) in advanced BRAF-mutated melanoma treated with BRAF/MEK inhibitors. Seventy-five patients with metastatic melanoma were enrolled in a multi-center trial and treated with vemurafenib/cobimetinib. [18F]FDG-PET/CT scans were performed at baseline, week-2, and week-7. Imaging analysis included SUVpeak, MTV, and TLG of summed metastases, as well as percentage changes over time (∆). Baseline median PET-parameters were SUVpeak 12.59 (range 3.13–50.59), MTV 159mL (range 0-1897 mL), and TLG 1013 (range 1-13162). Baseline MTV was the strongest predictor (AUCT=6 months=0.714), while early changes in MTV, TLG, and especially week-7 ΔSUVpeak

BACKGROUND:The RAPIDO trial compared total neoadjuvant treatment (TNT) with preoperative chemoradiotherapy (CRT), both followed by total mesorectal excision, in patients with locally advanced rectal cancer (LARC). A higher locoregional recurrence (LRR) rate was observed after TNT. This study investigates factors contributing to the difference in LRR observed. METHOD:Patients with high-risk LARC received TNT (5 × 5 Gy followed by 6 × CAPOX or 9 × FOLFOX4) or CRT (25-28 × 1.8-2 Gy with concurrent capecitabine). Patients with a local R0 or R1 resection were included in this study. Sphincter-preserving surgery encompassed (low) anterior resection and Hartmann's procedure. The influence of baseline, surgical and pathological factors on LRR was evaluated. RESULTS:Of 920 randomized patients, 849 (430 versus 419 in the TNT and CRT arms) were eligible. The cumulative incidence of LRR at 8 years was 10.8% after TNT and 5.8% after CRT (HR 1.91). Following sphincter preserving surgery, 12.1% (TNT) and 4.8% (CRT) developed LRR (HR 2.60), compared to 8.5% versus 7.5%, respectively, after abdominoperineal resection. Distal resection margin rates (DRM) of 10 mm or less after sphincter-preserving surgery were similar in both arms (TNT 17.5% versus CRT 22.1%). However, a higher cumulative incidence of LRR was observed with a DRM of 10 mm or less after TNT (25.4% versus 1.8%; HR 15.51). Other factors were similar between treatment arms with respect to LRR. CONCLUSION:The difference in LRR between TNT and CRT mainly occurred in patients treated with sphincter-preserving surgery. Baseline information on the original tumour bed should be considered when determining the surgical approach after total neoadjuvant treatment.

Whole-body CD8+ T-cell PET imaging can detect spatial and temporal localization of CD8+ T cells. To obtain insight into early CD8+ T-cell response to immunotherapy in patients with melanoma, a highly immunogenic tumor, we performed serial PET imaging with the 1-armed CD8 antibody tracer 89ZED88082A. Methods: Immunotherapy-naïve adult patients with stage IV melanoma underwent PET scanning 2 d after receiving 10 mg of 89ZED88082A intravenously at baseline and 6-8 wk after initiation of standard-of-care immunotherapy. Tracer uptake in lesions, normal lymph nodes, and Waldeyer ring was assessed using SUVmax; other healthy tissue uptake was assessed using SUVmean Uptake in tumors and healthy lymph nodes was expressed as the geometric mean SUVmax per patient and in healthy tissue as SUVmean for all patients. Tumor response was evaluated in accordance with iRECIST version 1.1. Tumor tissue was immunohistochemically stained for CD8. Results: Serial imaging was performed for 10 of 11 enrolled patients. The geometric mean tumor SUVmax was 7.2 (95% CI, 5.6-9.4) before treatment and 7.3 (95% CI, 5.7-9.5; P = 0.89) during treatment, with spatial and temporal heterogeneity in tumor uptake. The spleen demonstrated the highest uptake among healthy tissues, and this value remained similar during treatment. After immunotherapy, 2 patients experienced a complete response, 7 a partial response, and 2 progressive disease. Changes in tumor uptake during treatment did occur but did not correlate with tumor response. Nine evaluable pretreatment tumor tissues showed a CD8-inflamed immune phenotype. Conclusion: Lesions demonstrated spatial and temporal heterogeneity in 89ZED88082A uptake within and among patients with melanoma.