Lars Fokdal

Background and purpose: Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy with limited treatment options for advanced or metastatic disease. Immune checkpoint inhibitors (ICIs) have shown durable responses in clinical trials, but evidence derives from small and highly selected populations. This study investigates the effectiveness and tolerability of pembrolizumab in an unselected real-world cohort. Patient/material and methods: This retrospective, multicenter cohort study evaluated the real-world efficacy, durability, and safety of pembrolizumab in Danish patients with advanced or metastatic SCCA treated between September 2018 and September 2023. A total of 37 patients, who received at least one dose of pembrolizumab for non-resectable, recurrent or metastatic disease, were included (89% ≥ 2nd line). Median age was 64 years, the majority were female (64.9%), and most tumours were human papillomavirus (HPV) (p16) positive (73.0%). Results: The objective response rate (ORR) was 13.5%, with two complete and three partial responses. The clinical benefit rate (CBR) was 48.6%, and two patients had durable responses exceeding 24 months. Median progression-free survival (PFS) and overall survival (OS) were 4.0 months 95% confidence interval (CI) (2.6–5.5) and 12.1 months 95% CI (7.6–15.2), respectively. Patients with good performance status and HPV-positive disease had significantly improved survival outcomes. Treatment was well tolerated, and no treatment-related deaths were reported. Interpretation: In this real-world cohort, pembrolizumab demonstrated durable responses in a subset of patients with advanced SCCA and an acceptable safety profile. Outcomes were comparable to clinical trial data, indicating modest activity. Findings support using pembrolizumab as a treatment option in selected patients, but further evidence is needed to refine its role.

All identified pathogenic variants in the samples analyzed.

Background: Rectal bleeding is a well-known adverse event following pelvic external beam radiotherapy (EBRT) for prostate cancer. This study investigates risk factors for rectal bleeding and validate our current rectal dose constraints in a real-world setting. Material and methods: This prospective study includes 248 prostate cancer patients who received EBRT between 2017-2022. EBRT consisted of 56 Gy/39 fractions to the prostate, elective lymph nodes, and seminal vesicles with an integrated boost of 78 Gy to the prostate alone (≤T3a) or to the prostate and seminal vesicles (T3b). Rectal dose constraints were V50 Gy ≤50%, V70 Gy ≤20%, and V74 Gy ≤12%. Rectal bleeding was recorded at baseline and regularly duringfollow-up and included staff reported morbidity and patient reported outcome measures. Risk factors were evaluated in multivariate cox regression analysis. Results: Median follow-up was 18 months (range 1-61 months). Sixteen percent (CI:11%;22%) of patients reported rectal bleeding as “rarely”, 4%(CI:2%;8%) “about half the time”, 0% “usually”, and 2%(CI:0%;4%) “always”. Five percent reported rectal bleeding as bothersome. It was possible to comply with current rectal dose constraint (V74 Gy ≤12%) in 99.6% of all patients. Body mass index (BMI) (BMI:25-29.9, HR:0.54(CI:0.30;0.98), p=.044 or BMI>29.9, HR:0.40(CI:0.20;0.79), p=0.008)) were predictors for rectal bleeding. Interpretation: Patient-reported rectal bleeding is common after prostate cancer radiotherapy. High BMI was a protective factor against rectal bleeding. No correlation was observed between rectal dose-volume constraints and the occurrence of rectal bleeding, suggesting that a rectal high-dose constraint of V74 Gy ≤12% is an adequate threshold to minimize patient-reported rectal bleeding.

All identified pathogenic variants in the samples analyzed.

Oncoplot showing pathogenic gene alterations. The plot is split into groups by cellular pathways affected by the alteration on the vertical axis and clinical outcome (clinical benefit: PFS ≥12 months, no benefit: PFS ≤6 months) on the horizontal axis. Each column represents one patient. In total, 81 patient samples. See color guide reflecting specific alterations below the plot. # = Reason of “end of treatment” other than progressive disease. Integer “HRD-status and GIS” = the exact GIS reported by MyChoice.

Flowchart showing patients included in final gene panel analysis. * Formalin-fixed paraffin-embedded. ** TSO500 gene panel by Illumina.

BRCA1 (top) and BRCA2 (bottom) with variants found in AVANOVA1&2 colored by treatment response (see legend). BRCA1: Transcript NM_007294.4. In total, 1,863 aa. RING domain (aa 2–101), PALB2-binding domain (also called coiled-coil domain; aa 1,391–1,424), BRCT repeats (aa 1,650–1857), and exon 11 (aa 224–1,366). BRCA2: Transcript NM_000059.4. In total, 3,418 aa. PALB2-binding domain (aa 10–40), DNA-binding domain (aa 2,481–3,186), and exons 10 and 11 (aa 266–2,281).