Background/Objectives: Radiotherapy de-escalation is an established strategy in the management of early breast cancer, supported by randomized evidence predominantly derived from older patient populations. Younger women remain underrepresented in de-escalation trials, despite exhibiting less favorable clinicopathological characteristics associated with increased locoregional recurrence and inferior survival. The objective of this systematic review is to assess the available evidence regarding the safety and implementation of radiotherapy de-escalation strategies in younger patients with early breast cancer. Methods: A literature search following the PRISMA 2020 guidelines was performed to identify studies evaluating radiotherapy de-escalation strategies in younger breast cancer patients. Ongoing and recently completed trials were identified through ClinicalTrials.gov. Epidemiological data, randomized trials, and current clinical guidelines were reviewed. Results: Younger age at diagnosis is consistently associated with more aggressive tumor biology, higher rates of nodal involvement, unfavorable molecular subtypes, and worse survival outcomes. Among de-escalation approaches, moderate hypofractionation (15-16 fractions) is supported by randomized evidence and contemporary guidelines and can be applied irrespective of age. In contrast, evidence supporting ultra-hypofractionation, partial breast irradiation, and omission of radiotherapy in younger patients remains less robust, as these strategies have largely been evaluated in older or postmenopausal populations. Conclusions: Radiotherapy de-escalation in younger patients with breast cancer should be approached with caution. While moderate hypofractionation appears safe regardless of age, more aggressive de-escalation strategies lack adequate evidence in women under 50 years, particularly those under 40. Further prospective studies with sufficient representation of younger patients are required to clarify the role of radiotherapy de-escalation in this population.

Gynecological cancer requiring management during pregnancy is rare, with an estimated incidence of 2 to 5 per 100,000 pregnancies in the first trimester. Balancing maternal and fetal health in these cases can be difficult, and management strategies differ from nonpregnancy cases. Management strategies are typically determined by maximizing benefit to the mother while minimizing harm to the fetus, considering the extent of the cancer, available treatment options for each type of cancer, and the gestational age of the fetus. This article is a guideline presenting the highest standard of evidence for the management of these cases, although the authors recognize that following these recommendations is not always possible in all areas of the world. These guidelines address imaging, pathology, surgery, medical oncology, obstetrics, radiation therapy, psychology, patient perspective, and pediatric follow-up for ovarian, cervical, and vulvar cancers during pregnancy. The guidelines in this article were developed using the European Society of Gynecological Oncology (ESGO) via the ESGO Guideline Committee. This consists of a multidisciplinary international development group that uses scientific evidence and expert consensus, as well as an external international review process. A systematic review was performed as part of the creation of these guidelines, including relevant studies published between January 2014 and June 2024. In cases where evidence was unclear, professional experience and expertise were used to fill the gap. General guidelines included discussing treatment with a multidisciplinary team, patient and partner counseling being a priority (including diagnostic and treatment plans, potential alternatives, risks and benefits, and side effects), workup and treatment being conducted at a specialized center, patients receiving care as close as possible to nonpregnant patients, taking into account individual modifications as necessary, prioritizing research with these cases, and registration of all cancer cases during pregnancy. The incidence of cancer during pregnancy is not decreasing, and thus, practitioners should be aware of these possible complications of pregnancy. Recommendations include investigating symptoms of cancer immediately and thoroughly, as well as preserving the pregnancy because pregnancy does not worsen the prognosis of gynecological cancers. Imaging guidelines include ultrasound examination for diagnosis, with the reassurance of its safety during pregnancy, magnetic resonance imaging (MRI) for inconclusive ultrasound examination, referral to an experienced radiologist, repeated ultrasound examination for management planning, using ultrasound to evaluate patient response to neoadjuvant chemotherapy, and avoiding the use of gadolinium-based contrast agents, using diffusion-weighted MRI instead. In addition, the use of a lead apron for shielding is not recommended. The recommendations surrounding pathology include recording all relevant information on the pathology request form, referral for specialist opinion, and submission of the placenta for pathological examination after delivery. Surgical recommendations include locoregional anesthesia as a preferred method over general anesthesia and using a left lateral tilt of at least 15 degrees after 20 weeks of gestation. If procedures cannot be postponed, they should be performed during pregnancy even with an elevated risk to the fetus, though trauma to the uterus should be avoided. Minimally invasive procedures are preferred during pregnancy, when possible, though there is little evidence surrounding safe lengths and abdominal pressures; thus, surgical times and abdominal pressure should be minimized. Medical oncology guidelines include assessment of maternal and fetal health before each chemotherapy cycle, choosing a chemotherapy regimen based on cancer type, adapting standard treatment due to anticipated fetotoxic effects, and timing of chemotherapy to be after 12 weeks of gestation and before 35 weeks of gestation. In terms of obstetrics, it is recommended to encourage the use of compression stockings or devices during surgery and prophylactic low-molecular-weight heparin both after surgery and after delivery. Preterm birth should be avoided if possible, and delivery should be timed 2 weeks after the last course of chemotherapy if possible. If preterm delivery is expected, corticosteroids should be administered for fetal lung development in accordance with standard care recommendations. Cesarean delivery is recommended in cases of vulvo-vaginal cancer in situ and invasive cervical cancer, and vaginal delivery can be considered in cases where cancer has been completely removed or is restricted to the ovaries. The effects of radiation should be considered in a risk/benefit assessment for this therapy during pregnancy, and pelvic or groin radiation therapy should not be performed if pregnancy preservation is desired. Limited delay of radiation therapy should be considered if it allows for standard treatment, but minimizing fetal exposure can be considered as well in urgent cases. If pregnancy preservation is not desired, radiation therapy in combination with feticide or uterine evacuation can be proposed. Oncopsychologists should be included in the multidisciplinary team managing cases of gynecological cancer in pregnancy, and regular screening should be performed along with support offered at every stage of treatment during and after pregnancy. Patients and their partners should be included in treatment decisions and educated and consulted about their care. Long-term monitoring is recommended for children exposed to chemotherapy or radiation in utero, including assessments of hearing, cardiotoxicity, and neurodevelopmental delays.

In view of the shifting standard of care for non-small cell lung cancer (NSCLC), we aimed to capture the evolution of the epidemiological and systemic treatment (ST) landscape in Greece. This non-interventional, single-country, multicenter, retrospective study, collected high-level aggregate data for adult patients who were newly diagnosed with histologically/cytologically confirmed Stage I-IV NSCLC between 01-Jan-2016 and 31-Dec-2020 (index period) at leading oncology clinics across the country. Overall, 10,644 patients were newly diagnosed with NSCLC during the entire 5-year index period at the 18 participating sites (63.8

Sacizuzumab Tirumotecan is a novel antibody-drug conjugate targeting TROP2 glycoprotein, which is highly expressed across malignant cells. Sacizuzumab Tirumotecan has already demonstrated promising clinical activity in combating breast and lung cancer, and it is currently under evaluation for use against gynecologic malignancies. This review aims to highlight the therapeutic potential of Sacituzumab Govitecan in gynecologic malignancies and to summarize the most recent evidence supporting its clinical application. Ongoing phase III trials of Sacituzumab Tirumotecan include cervical, ovarian, and endometrial cancers. Preliminary safety data of Sacituzumab Tirumotecan indicates a manageable toxicity profile, with the most commonly reported adverse events including hematologic toxicity, oral mucositis, and alopecia. Mature data from Phase III trials are anticipated to clarify the impact of Sacituzumab Tirumotecan on overall survival, progression-free survival, and objective response rates. Additionally, biomarker analyses may enhance patient selection strategies and refine prognostic assessment in gynecologic oncology. Antibody-drug conjugates (ADCs) are an advent in the management of oncology patients. Sacituzumab Tirumotecan (sac-TMT/MK-2870/SKB264) is a promising new ADC undergoing clinical trials in solid tumors. Promising results have been published with the use of Sacituzumab Tirumotecan in gynecologic malignancies, mainly cervical, ovarian and endometrial cancers. More mature data from phase III trials are expected soon.

4568 Background: Ave 1L maintenance is a recommended treatment option for patients (pts) with aUC without progression after 1L platinum-based chemotherapy (PBC). In the JAVELIN Bladder Medley phase 2 trial (NCT05327530), 1L maintenance with Ave + SG (Trop-2–directed antibody-drug conjugate) improved progression-free survival (PFS) vs Ave mono (primary endpoint). In pts with aUC, presence of visceral metastases (including liver or lung) is associated with poorer prognosis. We report updated subgroup analyses from the primary analysis of JAVELIN Bladder Medley based on metastatic site. Methods: Pts with unresectable locally advanced or metastatic UC without progression after 4-6 cycles of 1L PBC were randomized 2:1 to receive Ave + SG or Ave mono, stratified by presence of visceral metastases at start of 1L PBC. Primary endpoints were investigator-assessed PFS (measured from randomization) and safety; overall survival (OS) was a secondary endpoint. For visceral and nonvisceral subgroups, PFS and OS data in the Ave mono arm were extended per protocol using propensity score–weighted data from the JAVELIN Bladder 100 phase 3 trial; extended data were not available for other subgroups. Results: At the start of 1L PBC, of 74 and 37 pts in the Ave + SG and Ave mono arms, respectively, 37 (50.0%) and 19 (51.4%) had visceral metastases, 20 (27.0%) and 11 (29.7%) had lung metastases, 17 (23.0%) and 7 (18.9%) had liver metastases, 17 (23.0%) and 11 (29.7%) had bone metastases, and 26 (35.1%) and 11 (29.7%) had lymph node–only disease. At data cutoff (Apr 28, 2025), in the Ave + SG and Ave mono arms, respectively, median follow-up for PFS was 15.7 and 25.1 mo. Across all subgroups, PFS was prolonged with Ave + SG vs Ave mono (Table); OS analyses were immature. In the Ave + SG and Ave mono arms, respectively, grade ≥3 treatment-related adverse events occurred in 72.2% and 5.6% of pts with visceral metastases, 57.9% and 0% of pts with lung metastases, 82.4% and 0% of pts with liver metastases, 82.4% and 0% of pts with bone metastases, 70.3% and 5.6% of pts with nonvisceral metastases, and 76.9% and 9.1% of pts with lymph node–only metastases. Conclusions: In the primary analysis of JAVELIN Bladder Medley, Ave + SG as 1L maintenance improved PFS vs Ave mono, irrespective of metastatic site. Clinical trial information: NCT05327530 . PFS, median (95% CI), mo Ave + SG Ave mono HR (95% CI) Site of metastases at start of 1L PBC Visceral* 9.03 (5.62-13.80) 2.20 (1.91-3.71) 0.49 (0.28-0.84) Nonvisceral 14.69 (7.43-NE) 7.33 (4.21-11.10) 0.61 (0.33-1.13) Lung 8.77 (4.17-9.46) 1.81 (0.07-9.26) 0.43 (0.17-1.09) Liver 8.77 (5.55-9.36) 2.69 (1.91-NE) 0.48 (0.17-1.32) Bone 9.26 (5.49-17.64) 2.33 (0.07-5.45) 0.40 (0.16-0.99) Lymph node only 14.00 (7.43-NE) 7.59 (1.87-NE) 0.65 (0.26-1.66) *Pts could have ≥1 site of visceral metastases.HR, hazard ratio; NE, not estimable.

Objective The phase 3 DUO-E trial demonstrated statistically significant progression-free survival (PFS) benefit with carboplatin/paclitaxel plus durvalumab followed by durvalumab with/without olaparib maintenance versus carboplatin/paclitaxel alone in advanced/recurrent endometrial cancer. We report exploratory analyses of key biomarkers and histology in the mismatch repair proficient (pMMR) subpopulation. Methods Patients were randomised 1:1:1 to carboplatin/paclitaxel (control arm), carboplatin/paclitaxel plus durvalumab followed by durvalumab (durvalumab arm) or carboplatin/paclitaxel plus durvalumab followed by durvalumab plus olaparib (durvalumab + olaparib arm). The presence of and relationship between selected biomarkers and histology, and PFS were investigated in the pMMR subpopulation. Results Biomarkers of interest (programmed death-ligand 1 [PD-L1] expression and mutations in BRCA1/BRCA2 genes, homologous recombination repair genes, DNA polymerase epsilon and tumour protein 53 [TP53m]) were evaluable in 486/575 patients in the pMMR subpopulation, with 84% (n = 407) positive for ≥ 1 biomarker; PD-L1 positive (67%) and TP53m (59%) were the most prevalent biomarkers. In the biomarker-known subpopulation, 52% and 27% of patients had tumours of endometrioid and serous histology, respectively. In exploratory analyses, PFS hazard ratios were improved versus control for both treatment arms across multiple biomarker and histology known subgroups, and favoured the durvalumab + olaparib arm in the majority of assessed biomarker/histological subgroups. Conclusions The DUO-E pMMR subpopulation was highly heterogeneous with frequent overlap of biomarkers and histology. Consistent with the primary analysis, durvalumab plus olaparib improved the PFS benefit observed with durvalumab versus control across a range of biomarker and histological subgroups.

Background: Uterine serous carcinoma (USC) represents a rare but aggressive subtype of endometrial cancer, accounting for a disproportionate number of disease-related deaths. Although molecular classification has improved risk stratification, prognostic heterogeneity highlights the need for new prognostic markers. Methods: We retrospectively analyzed 83 patients with USC treated at our institution between 1 January 2015 and 31 December 2023. Clinicopathological characteristics, treatment strategies, molecular biomarkers accessed by immunohistology (TP53, ER, PR, HER2, and MMR status), and survival outcomes were collected. Patients were first staged by FIGO 2009 and retrospectively reclassified by FIGO 2023. Disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) were assessed using Kaplan-Meier and Cox regression analyses. Results: The majority of patients were presented with advanced disease (FIGO stage IIIC-IV). TP53 mutations were found in 88% of cases, HER2 amplification in 18%, and ER expression in 57.8%. ER-positive patients showed significantly improved DFS in the adjuvant setting compared with ER-negative patients, whereas no significant associations were observed for first-line PFS or OS in multivariable analyses. HER2 amplification was not associated with inferior survival in our cohort. The advanced stage remained an independent predictor of worse OS. Conclusions: USC is a biologically heterogeneous disease, and its treatment should be guided by its molecular profile. ER expression identifies a subset of patients with improved DFS, suggesting potential prognostic relevance in this high-risk histology.

The development of endocrine resistance represents a major obstacle when treating hormone receptor-positive breast cancer. The tumor microenvironment (TME), represented by cancer-associated fibroblasts (CAFs) in this context, has recently been proposed as a key mediator significantly contributing to resistance against currently available endocrine therapies. The exact mechanisms behind this interaction are not fully understood; specific breast CAF subtypes have been linked to it, such as CAFs lacking the expression of the glycoprotein CD146 or maintaining the expression of CD63. Other proposed mechanisms include signaling pathways aberrantly activated in CAFs, epigenetic modifications mainly in the form of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), and paracrine signaling, all limiting endocrine modulation effectiveness. Strategies aiming to simultaneously target CAFs and endocrine signaling in luminal breast cancer are currently being developed. Fibroblast growth factor receptor (FGFR) targeting in combination with endocrine inhibition has already entered the clinical trial landscape. However, CAFs are a highly diverse and heterogeneous cell population, making their targeting complex and difficult to implement in clinical practice.

BACKGROUND:Fulzerasib, a KRASG12C inhibitor, has shown clinical activity in previously treated non-small-cell lung cancer (NSCLC). Clinical studies indicate that combining a KRASG12C inhibitor with an anti-EGFR antibody is effective in colorectal cancer; however, its benefit in NSCLC remains to be explored. METHODS:This single-arm, phase 1b/2 trial enrolled patients at 30 medical centres in Spain, Italy, and Greece. Eligible patients had KRASG12C-mutated NSCLC with no previous systemic anti-tumour therapy for advanced or metastatic disease and were aged 18 years and older; had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1; had an Eastern Cooperative Oncology Group performance status of 0 or 1; and had a life expectancy of 3 months or more. Enrolled patients received 600 mg oral fulzerasib twice daily plus 500 mg/m2 intravenous cetuximab every 2 weeks. The primary endpoint was investigator-assessed objective response rate per RECIST 1.1 assessed in the full response analysis set. The study was registered with ClinicalTrials.gov (NCT05756153) and is complete. FINDINGS:Between April 23, 2023, and April 15, 2024, a total of 60 patients were screened, and 47 patients (78%) received treatment. The median age was 68 years (IQR 59-72); 25 patients (53%) were male and 22 (47%) were female. 45 (95%) patients were current or former smokers. As of Jan 14, 2025, the median follow-up time and treatment duration were 12·8 months (90% CI 11·6-14·6) and 10·1 months (IQR 6·3-13·0) months, respectively. The confirmed objective response rate was 69% (90% CI 56-80). Treatment-related adverse events (TRAEs) occurred in 41 (87%) of the 47 patients (grade 3 in seven [15%]). No grade 4 or 5 TRAEs were observed. TRAEs led to drug discontinuation in three (6%) patients, with only cetuximab being discontinued. INTERPRETATION:In treatment-naive KRASG12C-mutated NSCLC, fulzerasib plus cetuximab showed encouraging activity with a favourable safety profile. The combination is currently being planned for investigation in a phase 3 study. FUNDING:Zhejiang GenFleet Therapeutics.

1001 Background: Imlunestrant (imlu) is a next-generation, brain-penetrant, oral selective estrogen receptor degrader. The EMBER-3 trial, in patients (pts) with ER+, HER2- ABC who had disease progression on or after aromatase inhibitor-based therapy, showed significant progression free survival (PFS) improvement with imlu vs standard therapy (SOC, fulvestrant or exemestane) in pts with ESR1 mutations ( ESR1 m), and with imlunestrant+abemaciclib (imlu+abema) vs imlu in all pts, regardless of ESR1 m. Exploratory PRO analyses are presented here. Methods: EORTC QLQ-C30 was administered at baseline (BL) and every 8 weeks until treatment discontinuation. Prespecified QLQ-C30 analysis used a longitudinal mixed model for repeated measures to calculate mean change from BL in pts with BL and ≥1 post-BL score. PRO-CTCAE (diarrhea frequency) was administered weekly, reporting 0 (never) to 4 (almost constantly). PRO-CTCAE (injection site reaction [ISR]) was administered to fulvestrant recipients weekly for 2 weeks post-injection, reporting yes/no (pain, swelling, redness). Descriptive analysis was used for PRO-CTCAE. Results: In pts with ESR1 m, imlu monotherapy was associated with many improved or maintained EORTC QLQ-C30 scores, whereas scores with SOC were declined or maintained. Specifically, pts with ESR1 m on imlu had improved global health status (GHS)/quality of life (QOL) and physical function (PF) scores, while scores with SOC declined (mean change differences between treatments: 9.9 [0.1, 19.7] and 6.2 [-0.8, 13.1], respectively). These PRO findings mirror the PFS findings in this group. In the overall population, GHS/QOL scores declined similarly with imlu vs SOC (mean change differences: 0.5 [-4.7, 5.7]), while PF scores were maintained with imlu vs a slight decline with SOC (mean change difference: 2.5 [-1.1, 6.1]). Most fulvestrant recipients (72%) reported ISR at any time while on treatment, with a mean of 31% during the first week of the first 6 cycles. Imlu+abema vs imlu showed broadly similar declines in all pts, with minimal mean change differences in GHS/QOL and PF scores (0.8 [-7.4, 5.9]; -2.2 [-6.6, 2.2], respectively). Pts reported similarly low rates of “frequent” or “almost constant” diarrhea with imlu (3%) and SOC (2%) and higher rates with imlu+abema (22%). Conclusions: PROs from EMBER-3 demonstrated that patients with ESR1 m had better GHS/QOL and PF with imlu vs SOC, mirroring efficacy results. While the frequency of CTCAE defined ISRs was low, the high rate of PRO-CTCAE ISR demonstrates that this clinically relevant adverse event is underappreciated by physicians. Additionally, all pts had generally comparable GHS/QOL and PF with imlu+abema vs imlu. Overall, these results support the efficacy and safety of imlu compared to existing SOC. Clinical trial information: NCT04975308 .

Left-sided portal hypertension or segmental portal hypertension is a rare cause of upper gastrointestinal bleeding. The present study reports a case of isolated gastric variceal haemorrhage and hypersplenism, due to left-sided portal hypertension induced by inflammatory myofibroblastic tumour (IMT)-associated splenic vein compression. IMT is an rare mesenchymal neoplasm of intermediate malignant potential that can develop in any location, frequently remaining entirely asymptomatic until it reaches a size that leads to complications. To the best of our knowledge, this is the first case reported of an IMT involving both the spleen and the pancreas. In this patient, splenectomy and partial pancreatectomy were both diagnostic and curative for IMT, and no adjuvant therapy was followed. This case report, along with a short review of the current knowledge on IMT features, contributes towards the understanding and diagnosis of this rare entity with diverse clinical presentations.

Prostate cancer is the second most common cancer, affecting millions of men globally and having a significant burden on health care systems. During recent years, the rapid development of the nuclear medicine field and the wide use and application of positron emission tomography combined with computed tomography (PET/CT) have significantly changed the diagnosis, treatment approach and patient outcomes. Semiquantitative analysis in PET/CT imaging quantifies the load of the disease in patients diagnosed with prostate cancer without measuring the precise amount of a radiotracer injected into the patient; instead, there is an indirect evaluation of the radiotracer using semiquantitative indices. Beginning with the standard uptake value (SUV) in Fluorodeoxyglucose (FDG) PET/CT, various semiquantitative measures have been created and are now used for analyzing different radiotracers. The purpose of this review is to provide an overview of the importance of the semiquantitative analysis in PET/CT imaging with the use of prostate-specific radiotracers at the initial staging of prostate cancer, as well as in biochemical recurrence and in the metastatic state.

Approximately 1 in 10 women diagnosed with breast cancer before the age of 35 carry germline BRCA pathogenic/likely pathogenic variants. Poly (ADP-ribose) polymerase (PARP) inhibitors have been recently approved in the treatment of both early and advanced breast cancer. However, there are no published cases of exposure to PARP inhibitors during pregnancy. Treatment with PARP inhibitors during pregnancy is currently contraindicated and can potentially harm fertility in young women with breast cancer. We here summarize all clinical and preclinical data on the effect of PARP inhibitors on pregnancy, fertility and breast-feeding to provide guidance on their optimal use in women of childbearing potential.