Background Pharmacological cancer risk reduction has received far less investment than therapeutic oncology and only a few agents have entered routine practice. Understanding the predictors of positive outcomes of previous trials and issues faced is critical to future developments. Methods This systematic review (PROSPERO CRD420250650276) included all phase III randomised controlled trials enrolling cancer-free adults over the past 45 years, evaluating pharmacological agents and whose primary or major secondary endpoint was directly related to cancer risk reduction. To predict trials’ ‘success’, defined here as meeting the prespecified cancer risk reduction-related endpoint within the planned timeline, we used the Least Absolute Shrinkage and Selection Operator followed by multivariable logistic regression. Results Ninety-two trials comprising 659 904 participants were included, of which 46 (50.0%) met their primary endpoint. Success rates varied by therapeutic class: vitamins (9 of 38, 23.7%), endocrine therapies (15 of 20, 75.0%), nonsteroidal anti-inflammatory drugs (8 of 13, 61.5%), human papillomavirus vaccines (8 of 9, 88.9%) and anti-infective agents (5 of 8, 62.5%). Proportionally, breast (76.5%), cervical (72.7%) and oesophagogastric (58.3%) cancer risk reduction trials had the highest success rates versus 23.7% for vitamins trials. Adherence was highest for vaccines [median 95%, interquartile range (IQR) 93%-96%] and lowest for endocrine therapies (median 70%, IQR 65%-78%). Major safety issues arising for a dozen of the drugs limited their approval (n = 5) and use. In the multivariable analysis, the odds of success increased for trials with pharmaceutical sponsorship [odds ratio (OR) 5.30, 95% confidence interval (CI) 1.01-35.77] and decreased for non mechanism-specific drugs and for studies with lower pretrial evidence (OR 0.30, 95% CI 0.10-0.90). Conclusions Although half of the pharmacological cancer risk reduction trials conducted so far have shown positive results, only a handful have led to regulatory approval. Trial success was driven by more targeted strategies and strong preliminary evidence, underscoring the need for mechanism-driven, strong-evidence development pathways in cancer risk reduction.
The Breast Cancer Susceptibility Gene (BRCA)-associated tumors represent a constantly evolving and intriguing scenario in oncology, in which the availability of novel systemic treatment, mainly including the poly (ADP-ribose) polymerase (PARP) inhibitors, has enabled an improved survival benefit in clinical subgroups. The expanding regulatory approvals of PARP inhibitors have inevitably reshaped the clinical indications for BRCA testing, moving the BRCA1/2 profiling from the traditional and preventive workflows to therapeutic paths. Despite advances in technology and treatment, substantial limitations remain in current genetic and genomic tools for the detection of deleterious BRCA1/2 variants. Germline and tumor tissue testing provide only a snapshot of a patient’s disease, failing to capture the dynamic and longitudinal aspects of tumor clonal evolution. In this scenario, liquid biopsy (LB) profiling of BRCA1/2 genes, primarily as circulating tumor DNA, represents a highly active area of research potentially affecting many aspects of cancer screening, diagnosis, and monitoring in individuals who are carriers of BRCA1/2 deleterious variants. Beyond the attractive potential to surrogate the tumor tissue testing, to overcome the cancer spatial and temporal heterogeneity, and to monitor the tumor mutational profile over time, accurately detecting all clinically relevant BRCA genetic variants and epigenetic modifications using LB remains technically challenging.
BACKGROUND:Neoadjuvant chemoimmunotherapy is standard for resectable non-small-cell lung cancer (NSCLC) but response assessment is challenging due to pseudoprogression, which may lead to unnecessary cancellation of surgery. We characterized pseudoprogression and developed a clinical strategy to distinguish it from true progression after neoadjuvant immune checkpoint inhibitor (ICI) therapy. PATIENTS AND METHODS:We retrospectively analyzed data from 283 patients with resectable NSCLC receiving neoadjuvant ICI (n = 235) or tyrosine kinase inhibitor (n = 48) therapy from January 2021 to December 2023. Positron emission tomography-computed tomography (PET-CT) scans were acquired at baseline and preoperatively. Responses were evaluated using RECIST 1.1 and European Organisation for Research and Treatment of Cancer (EORTC) criteria. Predictors of pseudoprogression were evaluated using multivariable logistic regression. Model performance was assessed in an independent validation cohort (n = 95). RESULTS:By RECIST 1.1, 26 of 283 patients (9.2%) had progressive disease (PD), all in the ICI cohort. By EORTC criteria, the number with PD increased to 71 of 283 (25.1%). Despite PD, all 26 patients underwent R0 resection; complete pathological response (CPR) and major pathological response (MPR) rates were 53.8% and 65.3% compared with 30.0% and 49.0%, respectively, in patients without PD. Among 71 with progressive metabolic disease, 69 (97.2%) achieved R0; CPR and MPR were 38.0% and 54.9%, respectively. Primary-tumor progression had lower MPR than nodal or distant progression (23.1%, 58.2%, and 73.3%, respectively, P = 0.020). Pseudoprogression occurred in 7.2% based on CT, increasing to 16.2% with PET-CT. A ≥53.1% reduction in primary-tumor maximum standardized update value (SUVmax) identified pseudoprogression [area under the curve (AUC) 0.865, sensitivity 94.7%, specificity 74.1%]. A multivariable model combining change in SUVmax, longest diameter change, smoking status, and histology showed excellent discrimination (AUC 0.935) and remained robust in validation (AUC 0.859). CONCLUSIONS:Imaging-defined progression after neoadjuvant ICI may reflect pseudoprogression, most commonly nodal or distant lesions without primary tumor progression. A validated model incorporating primary-tumor metabolic response and clinical features improves discrimination of pseudoprogression and may support decision making to avoid inappropriate cancellation of potentially curative resection.
BACKGROUND:Uncommon EGFR mutations (ucEGFR mut) account for 10%-15% of epidermal growth factor receptor (EGFR) oncogenic alterations in non-small cell lung cancer (NSCLC) and display heterogeneous sensitivity to EGFR tyrosine kinase inhibitors. MATERIALS AND METHODS:Clinical, pathological, and molecular data from patients with advanced NSCLC harboring ucEGFR mut (excluding ex20 insertions) and treated with first-line osimertinib were retrospectively collected from the Italian ATLAS registry. RESULTS:From January 2019 to January 2025, 212 patients were included. Median age was 69 years (range 24-90); 61.3% were female and 47.6% had a smoking history. Exon 19 deletions/insertions (ex19 delins) were the most frequent ucEGFR mut (55.7%), followed by L816Q (10.8%), G719X (8.5%), and D761N (7.5%). Tumor protein p53 and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) comutations were present in 43.3% and 10.4% of cases. The overall response rate (ORR) was 66% [95% confidence interval (CI) 58-73], median progression-free survival (mPFS) was 18.3 months (95% CI 14.6-19.7), and median overall survival (mOS) was 34.5 months (95% CI 26.1-42.9). Patients with ex19 delins showed superior outcomes versus other ucEGFR mut: ORR (74.3% versus 55%, P = 0.007), mPFS (25.3 versus 12.6 months, P = 0.001), and mOS (41.7 versus 30.4 months, P = 0.03), as well as different resistance mechanisms. Targetable acquired alterations (mesenchymal-epithelial transition amplification and C797S mutations) were detected predominantly in patients with ex19 delins, leading to the use of second-line molecularly matched therapies mainly in this subgroup. Patients with ex19 delins showed similar survival outcomes (25.3 versus 25.4 months, P = 0.55) and resistance patterns compared with a cohort of patients harboring the common exon 19 deletion (ELREA) extracted from the ATLAS registry. Among ex19 delins, variants starting at codon 746 achieved longer survival compared with those starting at codon 747. CONCLUSIONS:Osimertinib exhibited meaningful differences in efficacy and resistance mechanisms across distinct ucEGFR mut. Notably, ex19 delins showed comparable survival outcomes and resistance patterns to classical ex19 deletions, albeit with heterogeneous osimertinib sensitivity depending on the deletion-insertion starting codon.
Background Detection of circulating tumor DNA (ctDNA) following curative-intent therapy is prognostic of disease recurrence in early-stage breast cancer (EBC). An ultrasensitive structural variant (SV)-based ctDNA assay was evaluated previously in a 100-patient EBC cohort treated with neoadjuvant therapy, demonstrating high sensitivity, specificity, and a long lead-time to relapse. The stability of primary tumor-specific SVs at and after metastatic recurrence and their utility for longer-term ctDNA monitoring had not been established. Patients and methods An updated retrospective analysis of ctDNA dynamics was conducted in an expanded cohort of 121 patients with EBC treated with neoadjuvant therapy. Plasma samples were collected at key clinical timepoints and serially in several patients who experienced metastatic recurrence. Clinical variables were abstracted from medical records. Associations between ctDNA detection, dynamics, and clinical outcomes were evaluated in the early-stage and metastatic settings. Results Thirty of 121 patients experienced clinical recurrence (28 distant, 2 local) over a median follow-up of 4.2 years (range 0.5-8.8; 25 ctDNA evaluable with adjuvant timepoints). All patients with detectable ctDNA in the adjuvant setting developed metastatic recurrence (22/22). Median lead time from ctDNA detection to metastatic recurrence was 346 days (range 0-1937). Among recurrent cases, 79% of primary tumor-specific SVs (n = 17 patients, tumor fraction ≥0.1%) remained detectable in plasma [range 7% (1/14 SV)-100% (15/15); median: 92%]. ctDNA dynamics in the recurrent metastatic setting demonstrated a strong relationship with radiographic outcomes in evaluable patients (n = 9). Conclusion This SV-based digital PCR assay provided ultrasensitive ctDNA detection in an expanded EBC cohort, maintaining 100% positive predictive value for metastatic recurrence. In patients with recurrence, ctDNA dynamics were concordant with radiographic outcomes. Prospective studies evaluating the clinical utility of longitudinal ctDNA monitoring are warranted.
Background Mucosal melanoma (MM) is a rare and aggressive melanoma subtype that is understudied. The relationships between anatomical location, genomic alterations, stage at presentation, and survival remain incompletely characterized. Methods We carried out a retrospective single tertiary center study of 105 patients with histologically confirmed MM diagnosed between 1996 and 2025. Clinical and genomic data were analyzed to evaluate associations between anatomical location, mutational profile, stage at presentation, and survival outcomes, including melanoma-specific mortality. Results Lower-body tumors arising in the anus or genital areas were enriched for KIT and splicing factor 3 subunit B1 alterations, whereas NRAS mutations were distributed across anatomical regions. Among the two most common mutated genes, NRAS-mutant tumors were more likely than KIT-mutant tumors to present with metastatic disease [53% versus 19%; P = 0.046, odds ratio (OR) 4.7, 95% confidence interval (CI) 1.15-19.41]. Lower-body tumors were associated with worse overall survival (OS) than upper-body tumors (median 2.81 versus 8.40 years; OR = 0.05) and with higher melanoma-specific mortality. In multivariable analyses, upper-body location remained independently associated with improved OS (hazard ratio 0.14, 95% CI 0.05-0.36, P < 0.001). Conclusions Anatomical location of MMs and genomic alterations define biologically and clinically distinct subtypes.
Background In the phase III CodeBreaK 300 trial (NCT05198934), the combination of sotorasib, a KRASG12C inhibitor, and panitumumab improved clinical outcomes in patients with chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC). CodeBreaK 101 (NCT04185883) is a phase Ib trial wherein irinotecan, leucovorin, and 5-fluorouracil (FOLFIRI) was added to sotorasib and panitumumab in previously treated patients with KRAS G12C-mutated mCRC. Patients and methods Patients with KRAS G12C-mutated mCRC who received ≥1 prior systemic treatment were enrolled in CodeBreaK 101 subprotocol H dose-exploration and dose-expansion cohorts. In the dose-exploration cohort, patients received sotorasib (960 mg orally daily) plus panitumumab [6 mg/kg i.v. Q2W] and standard dose FOLFIRI (i.v. Q2W). This initial dose level was declared the recommended phase II dose and used in the dose-expansion cohort. The primary endpoint was safety, and secondary endpoints were efficacy and pharmacokinetics. Results A total of 46 patients were enrolled into the dose-exploration (n = 6) and dose-expansion (n = 40) cohorts [n = 21 (46%) female, median age, 54.0 (range, 36-76)]. Patients had received a median of two prior lines of therapy (range, 1-6) with approximately one-third each receiving the study regimen as second-, third-, or fourth-line-or-greater therapy. No dose-limiting toxicities were observed in the dose-exploration cohort at the initial dose level. In the 46 patients in both dose-exploration and dose-expansion cohorts, grade ≥3 treatment-related adverse events (TRAEs) occurred in 23 (50%) patients. The most common TRAEs were dermatitis acneiform (65.2%), dry skin (60.9%), and neutrophil count decreased/neutropenia (56.5%). Confirmed overall response rate was 56.5% [95% confidence interval (CI) 41.1-71.1], median progression-free survival was 8.3 months (95% CI 7.0-11.0), and median overall survival was 17.9 months (95% CI 13.0-23.3). Conclusions Sotorasib plus panitumumab and FOLFIRI demonstrated a manageable safety profile and promising antitumor activity in previously treated patients with KRAS G12C-mutated mCRC.
Background Paclitaxel is widely used in various cancers. This study aimed to evaluate paclitaxel oral solution versus paclitaxel injection in the second line of gastric cancer. Patients and methods Patients with unresectable, recurrent, or metastatic disease who have progressed after fluoropyrimidine-based first-line therapy were randomly assigned 1:1 (stratified by gastrectomy, Eastern Cooperative Oncology Group performance status and prior chemotherapy) to receive paclitaxel oral solution (200 mg/m2 twice daily on days 1, 8, and 15 of a 28-day cycle) or paclitaxel injection (175 mg/m2 on day 1 of a 21-day cycle). Dual primary endpoints included progression-free survival (PFS), assessed by a blind independent review committee, and overall survival (OS), with the noninferiority margin of the hazard ratio (HR) of 1.18 for PFS and 1.16 for OS. Results A total of 536 patients were randomly assigned into two groups (n = 268 each). Compared with paclitaxel injection, paclitaxel oral solution demonstrated a statistically significant and clinically meaningful improvement in OS [9.13 versus 6.54 months; HR 0.770, 95.5% confidence interval (CI) 0.635-0.934, P = 0.006], and was noninferior to paclitaxel injection in PFS (3.02 versus 2.89 months; HR 0.894, 95% CI 0.719-1.112, P = 0.311), along with a favorable and manageable safety profile. Paclitaxel oral solution showed a lower incidence of neuropathy, hypersensitivity reactions, alopecia, and musculoskeletal and connective tissue disorders. Treatment-related fatal adverse events were rare in both groups [four (1.5%) versus three (1.1%)]. Conclusions These findings support the use of paclitaxel oral solution as a viable alternative second-line option for gastric cancer.
Background Breast cancer (BC) mortality risk extends over decades; yet, the temporal prognostic patterns of histological grade across subtypes and stages remain unclear. Patients and methods Women with stage I-III BC diagnosed between 2000 and 2018 were identified from Surveillance, Epidemiology, and End Results registries (N = 767 218). Breast cancer-specific mortality (BCSM), as the primary endpoint, was analyzed using cumulative incidence functions including competing risk and annual hazard rates stratified by grade, estrogen receptor (ER) status, stage, and adjuvant chemotherapy. Restricted mean survival time differences were calculated to quantify absolute survival differences across follow-up intervals. Landmark survival analyses were carried out for 0 to <60, 60 to <120, and 120 to <180 months from diagnosis. Time-varying effects of grade were assessed through interval-specific modeling to evaluate nonproportional hazards. Results Overall, 23%, 44%, and 33% of cancers were grades 1, 2, and 3, respectively, accounting for 8%, 35%, and 57% of BC deaths. In each consecutive follow-up period, the contribution of grade 1 cancers to BCSM increased, and the contribution of grade 3 cancers decreased. Overall, 59% and 30% of deaths from grades 1 and 3 cancers, respectively, occurred after 5 years. In ER-positive disease, grade 3 tumors showed peak annual hazards between years 3 and 5, whereas grade 1 tumors had lower but sustained hazards extending beyond 10 years; the hazard curves converged between years 10 and 12. In ER-negative disease, early hazards were higher, and convergence also started earlier at years 5-8. Absolute risk was influenced by nodal status and tumor stage within each grade category and follow-up interval. Conclusion Grade 1 cancers show sustained risk beyond 10 years, whereas grade 3 cancers exhibit front-loaded risk. These temporal risk patterns, together with other clinical and genomic data, could inform extended endocrine therapy decisions and surveillance strategies.
Background Homologous recombination deficiency (HRD) is a critical biomarker for predicting response to poly (ADP-ribose) polymerase (PARP) inhibitors in high-grade serous ovarian cancer (HGSOC). Hence, genomic scar-based HRD testing must be implemented in routine clinical labs. This study aims to obtain a head-to-head comparison of some of the applications available for HRD status determination in a real-world clinical cohort to guide HRD testing standardization. Materials and methods HRD scores were obtained from HGSOC formalin-fixed, paraffin-embedded samples from the Molecular Prescreening Program at Vall d’Hebron Institute of Oncology (VHIO) using two approaches: VHIO-HRD (n = 229) and shallow sequencing-based HRD score (LSTsh-HRD; n = 123). Large-scale transitions (LST), telomeric allelic imbalance (TAI), and genomic loss of heterozygosity (LOH) were calculated using data from a custom hybrid-capture panel (VHIO-HRD score), and LST was determined from shallow whole-genome sequencing of a genomic library (LSTsh-HRD score). Validation was obtained by benchmarking against established and commercially available platforms. Tumor fraction (TF) was estimated using several computational tools. Results Optimized HRD status cutoff for VHIO-HRD (LSTVHIO-HRD + TAIVHIO-HRD + LOHVHIO-HRD) was set to ≥47 based on comparison with commercially available tools, whereas HRD status cutoff for LSTsh-HRD was predefined at ≥20. Despite differences in chemistry and scoring metrics, strong concordance in HRD classification was observed across assays. TF strongly influenced HRD performance, with optimal sensitivity at TF ≥0.4 for VHIO-HRD and ≥0.2 for LSTsh-HRD. Conclusions We validated that HRD scar quantification can be implemented across testing laboratories using assays with different library preparation chemistries and biomarker calculation algorithms. TF is a critical determinant of accurate HRD scoring; LSTsh-HRD quantification offers improved sensitivity in low-cellularity contexts, and VHIO-HRD enables status classification across the continuum of score values in samples with TF ≥0.4. A multiplatform, standardized HRD testing strategy may enhance biomarker-driven patient selection for PARP inhibitor therapies in HGSOC and other HRD-associated tumors.
In health care, artificial intelligence (AI) is emerging as a powerful tool to improve the quality of care, support health care professionals, and build a more streamlined and efficient health care system while also enhancing the patient experience. In particular, integrating AI into clinical practice through an innovative management approach like lean and change management could optimize diagnostic and therapeutic pathways, increase operational efficiency within hospitals, and promote more personalized, patient-centered care. At the same time, uncertainty remains about how these new technologies should be implemented in order to become broadly accessible in clinical practice. This expert opinion explores the potential role of AI in breast cancer patients’ care from the perspective of a team of Italian opinion leaders. The manuscript identifies two main areas of application: (i) AI solutions designed for direct patient interaction (i.e. conversational agents interacting with patients, providing informational and organizational support during the care journey and contributing to personalized care and improved patient quality of life) and (ii) AI solutions for clinical support to health care providers (i.e. tools or algorithms aimed at supporting physicians, reducing workload, and optimizing operational flows). When implemented alongside lean and change management strategies, these solutions have the potential to streamline care pathways and improve the satisfaction and interaction of patients and health care professionals, ultimately benefiting all stakeholders. The document also addresses the ethical, regulatory, methodological, and educational challenges associated with the implementation of AI solutions in clinical practice.
BACKGROUND:The size of tumour-negative regional lymph nodes (LNnegs) may be associated with the host antitumour immune response in patients with oesophagogastric adenocarcinoma (OGAC). In the OE02 trial, larger LNnegs were independently associated with improved overall survival (OS); however, the prognostic relevance of LNneg size has not been validated in an independent OGAC population. PATIENTS AND METHODS:Resection specimens from 1367 patients from two phase III trials (OE05, n = 652; ST03, n = 715) were analysed. The largest LNneg per patient was identified on digitised slides stained with haematoxylin-eosin using an automated segmentation pipeline. Lymph node ratio [LNratio; number of metastatic lymph nodes (LNs) divided by the total number of resected LNs] was calculated for patients with stage ypN1+ cancer. Anthracotic pigment burden was quantified using a deep learning model. Associations among LNneg size, primary tumour location, recurrence, and survival were evaluated. RESULTS:LNneg size and pigment burden differed by primary tumour location. LNnegs from oesophageal/junctional cancers were larger and had greater pigment burden than those from gastric cancers (all P < 0.0001). Larger LNnegs were associated with a lower recurrence rate (P = 0.033) and lower LNratio (P < 0.0001). Patients with LNnegs with a long axis diameter >10 mm had improved OS [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.70-0.93, P = 0.0147) and progression-free survival (HR 0.80, 95% CI 0.70-0.92, P = 0.0092). Presence of large LNnegs was independently prognostic after multivariable adjustment. CONCLUSIONS:This study validates LNneg size as a novel independent prognostic biomarker in patients with locally advanced OGAC treated with cytotoxic chemotherapy and surgery. Variation in LNneg size and pigment burden by primary tumour location may suggest anatomical or microenvironmental differences in LNneg biology that may affect LN assessment and immune-related characteristics. Further studies integrating quantitative microarchitectural and immune profiling of LNnegs are warranted to clarify the mechanisms driving LNneg enlargement and the potential functional relevance of pigment deposition.
Background The human epidermal growth factor receptor (HER) family is under evaluation as a therapeutic target in urothelial cancer (UC); the significance of expression patterns beyond those of HER2 is unclear. Patients and methods Tumour samples from a prospective randomised phase II-III trial (NCT00949455) were analysed by immunohistochemistry (IHC) and RNA profiling. Associations with molecular subtype, chemotherapy response, and overall survival (OS) were explored. The analyses were exploratory, and P values < 0.05 were considered relevant. Results A total of 446 tumours were tested for HER1/HER2, 77 for HER3, and 79 for HER4 expression. HER1–HER4 were positive (IHC 1-3+) in 89%, 80%, 77%, and 75% of tumours, respectively, with high expression (IHC 3+) in 34%, 12%, 26%, and 29%. Co-expression of all four receptors occurred in 61% of tumours, with concurrent high expression in 9%. Of the tumours, 96% expressed ≥2 receptors. Luminal tumours (n = 109) showed enriched HER2 expression (93% compared with 67%, P < 0.001), and basal tumours (n = 61) showed higher enriched HER3 expression (95% compared with 77%, P = 0.02). HER1 positivity correlated with better chemotherapy responses (P = 0.02) and HER3/HER4 positivity with poorer responses (P = 0.02 and P = 0.03, respectively). No differences in OS were observed. Conclusions HER1–HER4 are broadly and concurrently expressed in advanced UC, supporting antibody-drug conjugate development beyond HER2. Receptor expression did not correlate with OS.
Background PLATFORM is a prospective, open-label, multicentre, adaptive phase II trial assessing maintenance therapy in patients with advanced HER2-negative oesophagogastric adenocarcinoma after platinum-based first-line chemotherapy. Patient and methods After 18 weeks of platinum-based chemotherapy, patients with response or stable disease were randomised to surveillance (4 weekly visits) or rucaparib 600 mg tablet twice daily every 28 days. The primary endpoint was progression-free survival (PFS) (prespecified P value of 0.025). Secondary endpoints were safety and overall survival (OS). Exploratory translational analyses of homologous recombination deficiency (HRD) and somatic gene profiling are also reported. Results A total of 125 patients were randomised (surveillance: 62, rucaparib: 63). The median follow-up was 41 months. Median PFS was 2.8 months for surveillance and 4.2 months for rucaparib [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.49-1.02, P = 0.031]. There was no difference in OS (HR 1.15, 95% CI 0.77-1.72, P = 0.247). Grade ≥3 adverse events (AEs) occurred in 23% of surveillance and 32% of rucaparib patients. Treatment-related AEs were reported in 84% of patients in the rucaparib arm; 22% of which were grade 3-4. Most frequent grade 3-4 AEs were anaemia, fatigue, infection, and neutropenia. Adequate tissue for HRD analysis was available in 51/125 (40.8%) patients (surveillance: 20, rucaparib: 31). Five patients (9.8%) were HRD-positive, 41 (80.4%) HRD-negative, and 5 (9.8%) had inconclusive results. Among HRD-positive patients, four were treated with rucaparib and had PFS durations of 2.6, 3.0, 8.3, and 10.6 months, respectively. TP53 was the most frequently detected somatic alteration, followed by SMARCA4 and ARID1A. Conclusion Compared with surveillance, maintenance rucaparib following first-line chemotherapy in patients with advanced HER2-negative OGA did not significantly improve PFS with no observed difference in OS. Translational analyses were limited by small sample size, and no clear associations with clinical outcomes were identified.
Background Extensive-disease small-cell lung cancer (ED-SCLC) is an aggressive disease with limited effective therapeutic options. Clinical trials suggest an additive effect of chemotherapy and immunotherapy in SCLC, although the magnitude of benefit seems to be limited. Considering the prolonged peripheral persistence of anti-PD-(L)1 blockade, we wanted to investigate the impact of prior immunotherapy exposure on the efficacy of second-line chemotherapy. Patients and methods Using the Epidemio-Strategy and Medical Economics lung cancer national real-world database, we selected ED-SCLC patients diagnosed between 17 February 2010 and 4 December 2023 who had received at least two lines of treatment for a metastatic disease with platinum-based regimens in the first-line setting. Second-line real-world progression-free survival (rw-PFS) and overall survival (OS) were analyzed according to first-line immunotherapy exposure using a multivariable Cox proportional hazards model and a propensity score-weighted sensitivity analysis. Results The study included 2051 patients with ED-SCLC: 638 (30%) in the immunotherapy-pretreated group and 1413 (70%) who received only first-line chemotherapy. Multivariable analysis showed no significant difference in second-line median rw-PFS between immunotherapy-pretreated patients [2.9 months, 95% confidence interval (CI) 2.7-3.3] and chemotherapy-only pretreated patients (2.5 months, 95% CI 2.4-2.7) (hazard ratio 0.94, 95% CI 0.85-1.04, P = 0.21). Similar results were observed in the propensity score adjusted Cox regression sensitivity analysis. A longer median OS from the start of second-line treatment was observed in immunotherapy-pretreated patients (6.6 months, 95% CI 6.1-7.1 compared with 5.7 months, 95% CI 5.4-6.1, P = 0.03) although, this result has not been confirmed in a more contemporary cohort. Conclusion This study showed no OS gain in second-line treatment among patients pretreated with immunotherapy compared with those who received chemotherapy alone as first-line treatment.
Therapies targeting human epidermal growth factor receptor 2 (HER2)-positive breast cancer have substantially improved outcomes. Nevertheless, marked biological and clinical heterogeneity continue to drive variability in prognosis and treatment sensitivity in early-stage disease. While contemporary guidelines provide broad management frameworks, uncertainty remains when tailoring treatment intensity to individual patients. HER2DX is a genomic-clinical test developed to support individualized decision-making in stage I-III HER2-positive breast cancer by integrating tumor biology with key clinical variables, including tumor size and nodal status. The assay generates three clinically relevant outputs: a prognostic relapse risk score, a pathological complete response (pCR) score, and an ERBB2 messenger RNA expression score. Since its original development, a substantial body of new evidence has emerged. Large international individual-patient-level meta-analyses have demonstrated independent associations of the HER2DX risk score with survival outcomes and of the pCR score with pathologically documented response beyond standard clinicopathological factors. Translational studies further show that HER2DX captures complementary biological features, such as hormone receptor signaling, proliferation, HER2 pathway activation, and immune infiltration and organization, that are not fully reflected by conventional pathology. Prospective evaluations, including prespecified analyses from the ECOG-ACRIN EA1181 CompassHER2 pCR trial and a multicenter real-world decision-impact study in Spain, provide additional evidence regarding the potential clinical application of HER2DX in both neoadjuvant and adjuvant settings. This updated review synthesizes current evidence and discusses practical, scenario-based considerations for integrating HER2DX into routine clinical practice to help optimize treatment intensity in early-stage HER2-positive breast cancer.
Background Treatment strategies for patients with metastatic breast cancer (MBC) are becoming increasingly complex, underscoring the need for reliable biomarkers to inform clinical decision making. Circulating tumor cells (CTCs) are well-established prognostic biomarkers in MBC, while tumor-derived extracellular vesicles (tdEVs) have recently demonstrated complementary significance in patients undergoing first-line chemotherapy. This study seeks to validate the complementary role of tdEVs in a larger patient population and establish a clinically relevant cut-off. Materials and methods Archived baseline CellSearch® images from 355 patients with MBC (NU16B06 study) were reanalyzed using the Automated CTC Classification, Enumeration and PhenoTyping (ACCEPT) software to quantify CTCs and tdEVs. Multiple tdEV cut-offs were evaluated for association with overall survival (OS), alone and with CTCs (≥5, CTChigh). The selected cut-off was validated in a subcohort of 385 patients from the phase III STIC CTC trial. Results In the NU16B06 cohort, higher tdEV levels were consistently associated with shorter OS, regardless of cut-off. As models performed similarly (Brier Score difference <0.005), a cut-off of >20 tdEVs/7.5 ml (tdEVhigh) was selected based on prior literature and clinical relevance. Patients with tdEVhigh had nearly doubled risk of death compared with tdEVlow. Combining tdEVs with CTCs identified distinct prognostic subgroups, with CTChigh/tdEVhigh patients showing the shortest OS. Among CTClow patients, tdEVhigh was associated with increased mortality risk. In the STIC CTC cohort, the cut-off was validated for OS and progression-free survival, with tdEVhigh consistently associated with poorer surivial. When combined, patients with CTChigh/tdEVhigh had the poorest outcomes, while tdEVhigh remained associated with worse prognosis among CTClow patients. Conclusion These findings support the use of tdEVs as complementary prognostic biomarkers to CTCs, potentially enhancing clinical trial design and informing treatment decisions in MBC.
