Annals of Oncology

Backgroundfollowing a first cutaneous squamous cell carcinoma (CSCC), one-third of patients develop new primaries, escalating their risk of metastasis and poor outcomes. However, current follow-up strategies are not risk-stratified, representing a critical gap in patient management. Objectiveto develop and validate a prognostic model to quantify individualized absolute risk of a first metachronous CSCC after an index tumor, accurately accounting for the high competing risk of mortality in this typically elderly population. Methodswe conducted a nationwide, population-based cohort study of 11,737 patients with a first histologically confirmed CSCC (Netherlands Cancer Registry, 2007-2008) with up to 10 years of follow-up. Data on subsequent tumors was retrieved via linkage to the Automated National Pathological Anatomy Archive (Palga). A Fine-Gray competing-risk model was developed using routinely available clinical and pathological predictors (age, sex, hematologic malignancy, basal cell carcinoma (BCC) and actinic keratosis (AK) history, presence of synchronous CSCC, primary tumor location, and differentiation). Model performance was assessed 10-fold cross-validation, quantifying discrimination (time-dependent C-index) and calibration. Resultsduring follow-up, 3,288 (28%) developed a first metachronous CSCC. The model identified key predictors: markers of cumulative UV-exposure (included AK history, [≥]5 prior BCCs), and immunosuppression (chronic lymphocytic leukaemia/small lymphocytic leukaemia). Male sex, presence of synchronous CSCC at baseline were also associated with higher risk. While discrimination was modest (cross-validated 5-year C-index: 0.64), the model demonstrated excellent calibration. Conclusionsthis competing-risk model provides individualized, well-calibrated absolute risk estimates for a first metachronous CSCC. Based on routinely available clinical features, it offers insight into how established predictors shape risk in this high-susceptibility population. External validation and the identification of novel predictors are necessary to further refine the model and support personalized dermatologic care.

BackgroundCutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer and is associated with considerable morbidity. Population-based data analysis in Germany has largely focused on incidence and trends. ObjectivesTo assess incidence, anatomical site- and T-stage distribution, histological subtypes of cSCC in Germany, with a focus on sex- and age-group specific patterns and regional differences. MethodsA total of 213,935 first primary invasive cSCC cases diagnosed between 1986 and 2019 were analysed from four federal states of Germany with complete case ascertainment. Crude and age-standardized incidence rates (CIR, ASIR) were calculated, and subgroup analyses were performed by sex, anatomical site, histological subtype, and T-stage and region. ResultsCIR increased by over 500 % from 1986 to 2015, with a steeper rise in women. Incidence plateaued after 2015 in most states, except for a delayed increase in Saarland. The face (ICD-10 C44.3) was the most frequent tumor site showing equal incidence in males and females. T1 tumors predominated (88.6 %), although staging data were incomplete in 33.5 % of cases. Regional and sex-based differences were observed in both T-stage and histological subtype distribution. Spindle cell and non-keratinizing variants were associated with more advanced stages. Cancer registry data did not count more than one cSCC and carcinoma in situ such as Bowens disease or actinic keratosis, leading to systematic underestimation of disease burden. ConclusionscSCC incidence has risen substantially in Germany, with significant variation by sex, region, and tumor type. Improved registry protocols incorporating multiple primaries, clinical staging, and early in situ lesions are essential for accurate surveillance and healthcare planning. Plain Language SummaryHow common is squamous cell skin cancer in Germany and how does it behave? We looked at cutaneous squamous cell carcinoma (cSCC), a common skin cancer that starts in the flat cells on the skins surface. It is the second most common skin cancer and the second most common cancer, affecting tens of thousands of people in Germany each year. We found that the registration of new primary cSCC tumors increased more than fivefold between 1986 and 2015. However, incidence rates plateaued from 2015 to 2019. Tumors most often appeared on the face, but the distribution by site differed between men and women. Men developed cSCC at younger ages and more frequently than women. Approximately 90% of tumors were diagnosed at an early stage, but staging information was missing for about 34% of cases. cSCC develops on chronically sun-damaged skin, and patients often have more than one tumor. There are also early skin changes that require treatment. Because cancer registries count only one tumor per person and ignore these early lesions, the true burden of treating patients with chronic sun damage is underestimated. We concluded that cSCC has become more common in Germany, with clear differences by sex, age, and region. Improving cancer registries to record all tumors will provide a more accurate picture of stage and subtype distribution. Recognizing high-risk groups, will help guide prevention, screening, and earlier treatment strategies. What is already known about this topic?Cutaneous squamous cell carcinoma (cSCC) is the second most frequent malignancy overall as well as the second most frequent skin tumor. Epidemiological research has long focused on Basal Cell Carcinoma (BCC) and cSCC conclusively. Recent research has addressed major differences in their epidemiology, highlighting differnces in incidence rates across genders and age groups. The largest data set on squamous cell carcinoma analysed so far was 145.000 cases. What does this study add?This study provides conclusive results on incidence, localization, tumor stages and histologic types comparing men, women and age groups based on large scale data with over 200,000 primary tumors over a period of more than 30 years. What is the translational message?Identification of gender- and age-specific risk patterns in cSCC enables the formulation of targeted prevention strategies, screening recommendations, and earlier diagnosis and optimized management of high-risk populations. The burden of morbidity and tumors associated with chronic actinic damage remains underestimated in current literature and cancer statistics. Demographic changes are expected to increase the disease burden substantially, although the exact magnitude remains uncertain.

This study compared machine-learning models for predicting recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) using clinicopathologic data from 1,621 stage I/II primary cutaneous melanoma patients. Our time-to-event models achieved concordance indices of 0.829 for RFS, 0.812 for DSS, and 0.778 for OS. Tumor thickness and mitotic rate were the most important predictors for RFS. Charlson comorbidity score and insurance type were critical for DSS and OS.

BackgroundBreast and ovarian tumors in patients with biallelic BRCA1 and BRCA2 mutations either by germline mutations accompanied by allele-specific loss of heterozygosity (LOH) or truncal somatic mutations respond to PARP inhibition. The repair of double stranded DNA breaks in tumors these tumors leads to homologous recombination deficiency (HRD), which can be measured using a variety of genomic and transcriptomic signatures. However, the optimal biomarker for BRCA deficiency is unknown. MethodsWe developed HRDex to determine HRD and its composite scores from allele specific copy number data analysis of whole exome sequencing (WES) data and examined the discriminatory ability of HRDex and other genomic and transcriptomic measures to identify BRCA deficiency in breast and ovarian tumors from The Cancer Genome Atlas (TCGA). ResultsHRDex scores have high correlation with SNP array based HRD scores in both breast and ovarian cancers. HRDex scores have high discriminatory accuracy to distinguish BRCA deficient breast tumors, similar to SNP array based scores (AUC 0.87 vs 0.90); however, discriminatory ability for ovarian tumors was lower (AUC 0.79 vs 0.90). HRD-LST had the best discriminatory ability of the three composite HRD scores. HRDex had higher discriminatory ability for identification of BRCA deficiency than RNA expression based scores (eCARD, tp53, RPS and PARPi7) in breast and ovarian tumors. Tumor mutational burden (TMB) was associated with BRCA deficiency in breast but not ovarian cancer. Combining HRDex score with mutational signature 3 modestly increased discriminatory ability for BRCA deficient breast and ovarian tumors (breast: AUC 0.90 vs 0.87; ovarian: AUC 0.83 vs 0.79). ConclusionsWES based HRD scores perform similarly to SNP array HRD scores, and better than other genomic or transcriptomic signatures, for identification of tumors with BRCA deficiency due to biallelic BRCA loss.

ImportanceMany patients will develop more than one skin cancer, however most research to date has examined only case status. ObjectiveDescribe the frequency and timing of the treatment of multiple skin cancers in individual patients over time DesignLongitudinal claims and electronic health record-based cohort study SettingVanderbilt University Medical Center database called the Synthetic Derivative, VA, Medicare, Optum Clinformatics(R) Data Mart Database, IBM Marketscan ParticipantsAll patients with a Current Procedural Terminology code for the surgical management of a skin cancer in each of five cohorts. ExposuresNone. Main Outcomes and MeasuresThe number of CPT codes for skin cancer treatment in each individual occurring on the same day as an ICD code for skin cancer over time ResultsOur cohort included 5,508,374 patients and 13,102,123 total skin cancers treated. Conclusions and RelevanceNearly half of patients treated for skin cancer were treated for more than one skin cancer. Patients who have not developed a second skin cancer by 2 years after the first are unlikely to develop multiple skin cancers within the following 5 years. Better data formatting will allow for improved granularity in identifying individuals at high risk for multiple skin cancers and those unlikely to benefit from continued annual surveillance. Resource planning should take into account not just the number of skin cancer cases, but the individual burden of disease. Key pointsQuestion: How many skin cancer patients are treated for more than one skin cancer and how soon after the first skin cancer do they occur? Findings: 43% of patients were treated for more than one skin cancer, the majority of which occurred within two years after the initial skin cancer. Just 3% of patients were treated for 10 or more skin cancers, but these patients accounted for 22% of all of the skin cancer treatments in the cohort Meaning: Nearly half of all skin cancer patients were treated for multiple skin cancers, while those without a second skin cancer after two years were less likely to be treated for a subsequent skin cancer within the next five years.

Acral melanoma (AM) is a rare subtype of melanoma associated with poor prognosis. However, inconsistent definitions--based on either anatomic location (e.g., palms, soles, subungual areas) or histopathologic subtype (e.g., acral lentiginous melanoma)--complicate prognostication, hinder treatment decision-making, and pose challenges for both clinical and translational research. This multi-institutional retrospective cohort study aimed to determine whether anatomic location or histologic subtype better predicts outcomes in AM. Distal extremity primary melanomas (n = 469) were matched 1:2 with cutaneous melanomas (CMs; n = 938). Cox proportional hazards models evaluated recurrence-free survival (RFS), melanoma-specific survival (MSS), and overall survival (OS). Of the distal tumors, 280 (59.7%) were ALMs, including 33 (11.8%) on non-subungual dorsal sites. Compared to CMs, acral surface melanomas had worse outcomes, while dorsal melanomas had similar outcomes, independent of histology. ALMs were associated with worse survival than superficial spreading melanomas (SSMs). In interaction models, ALMs on dorsal surfaces and all histologic subtypes on acral surfaces had worse MSS than non-distal SSMs. A revised definition of AM may better inform clinical management and future research.

To-date the genomic landscape of cutaneous pericytic tumours (PTs), which represent a morphological continuum, have not been comprehensively explored. In order to identify the driver events of PTs from across their histological spectrum, and potentially aid the current classification system, we sequenced DNA (whole-exome) and RNA (pulldown transcriptome) from tumour-normal pairs classified by two different dermatopathologists of angioleiomyoma (n=37), glomus tumour (n=30) and myopericytoma (n=11); with all sequencing data deposited in the European Genome and Phenome Archive.

BackgroundHigh risk (HR) basal cell carcinoma (BCC) subtypes have been associated with high recurrence rates that is felt to be better managed surgically. Specifically, Mohs Micrographic Surgery (MMS) is considered most effective for aggressive HR BCCs and superior to traditional nonsurgical techniques, including radiation. Recently, superficial radiation therapy with high resolution ultrasound image guidance called Image Guided Superficial Radiation Therapy (IGSRT) displayed high local control (LC) rates and is an emerging non-surgical alternative to MMS for non-melanoma skin cancer (NMSC). ObjectivesWe present the largest experience in the USA on treatment of BCCs using IGSRT and specifically evaluate if there are differences in LC between HR BCC versus non-HR subtypes using this technology. MethodsA retrospective analysis was conducted on 7,994 BCC lesions treated with IGSRT in the continental United States. We compared the results of BCCs treated with IGSRT separated by HR vs non HR groups including 339 HR BCC lesions and 7655 non HR BCC lesions. High risk was defined as infiltrative, micronodular, morpheaform, and sclerosing subtypes. Non-HR BCC included superficial, nodular, and not otherwise specified (NOS) subtypes. Local control (LC) rates at two and five years were calculated with actuarial life-table and Kaplan-Meier methods and statistically compared using log rank tests. ResultsIGSRT treatment of the HR BCC group showed no recurrences with two and five-year actuarial and KM LC rates all at 100%. In comparison, the non-HR BCC cohort achieved similar two and five-year actuarial LC rates of 99.71% and 99.24% (KM LC at 99.5% and 99.23%), respectively. No statistical differences in LC rates between the two cohorts (p=0.278 each) resulted. Patients tolerated treatment well with little or rare high grade RTOG toxicity reported in both cohorts. ConclusionHR BCC may be treated just as effectively as low risk BCC using IGSRT and presents a viable alternative to MMS. The targeted approach using IGSRT, incorporating high resolution dermal ultrasound (HRDUS), appear to enhance treatment accuracy and effectiveness demonstrating high LC rates in all subtypes of BCC comparable to MMS and is a viable non-surgical option. Plain language summary Effectiveness of a non-surgical skin cancer treatment using an image guided form of radiation modality on all subtypes of basal cell skin cancerRecent studies using a non-surgical treatment combining low penetrance radiation with ultrasound called Image Guided Superficial Radiation Therapy (IGSRT) showed promise in curing Basal Cell Cancer (BCC) of the skin, which is the most common skin cancer worldwide afflicting millions annually. Recent studies on early stage (I, II) BCCs treated with IGSRT (estimated combined total of [~]1900 BCC cases) appear to rival the best surgical treatment available called Mohs Micrographic Surgery ("Mohs" or MMS). Furthermore, certain subtypes of BCC appear to behave more aggressively with worse outcomes even with surgery and is generally felt inappropriate for radiation treatment. However, BCC subtypes were not specified in previous IGSRT studies. This study presents the largest experience (using medical chart review) in approximately 8000 BCC cases treated by IGSRT across the continental United States separated by aggressive vs non-aggressive subtypes for early stages (I, II) as well as more advanced (stage III) BCC cases to evaluate the efficacy and safety. This study confirms the high cure/control rate and safety of IGSRT for all subtypes of BCC which appear equivalent with Mohs (although the study was not meant to be a head to head comparison of the 2 different modalities). Moreover, the aggressive types of BCC showed similar (if not marginally better) cure rates than the more common non-aggressive BCC subtypes. The potential benefits to patients from this study show there is now a clinically proven non-surgical treatment with the same effectiveness as surgery for the most common cancer on the planet. Key PointsO_LIThis study provides evidence that backs up using IGSRT as a viable treatment option to MMS for both high risk and non-high risk BCC cases, achieving similar local control rates for both groups. C_LIO_LIIt highlights that high risk BCC is more sensitive to radiation therapies such as IGSRT than previously believed, challenging the conventional practice of surgical treatment. C_LI

IntroductionNon-melanoma skin cancer is the most common tumor. The combination of IFN-alpha 2b and IFN-gamma has been used as a new therapeutic opportunity to treat basal cell carcinomas and cutaneous squamous cell carcinomas. The aim of this report is to record prospectively the recurrence and new lesions rates in patients participating in phase II clinical trials. MethodsPhase II clinical trials (double-blind randomized one center study, InCarbacel-III, in patients with basal cell carcinoma; and open, non-randomized multicenter study, CECIN, in patients with cutaneous squamous cell carcinomas), with the use of the combination of IFN-alpha 2b and IFN-gamma were conducted to evaluate the efficacy, safety and the 5-year duration of clinical responses. Both studies were approved by institutional ethic committees and all the patients given their written informed consent. The investigational treatment was administered, peri- or intralesionally, three times per week, during 3 weeks. Clinical (RECIST 1.0) responses were evaluated three months after the end of treatment. ResultsThe combination of IFNs in InCarbacel-III study showed the best clinical response (complete response of 64.3%, overall response of 85.7%) with the highest doses (10.5 MIU); without patients recurrence at 5 years follow-up (3.5 MUI and 10.5 MUI groups). The frequency of new lesions decreased in the treated patients 8 times. In the CECIN study 14 patients achieved complete response and 4 partial responses (overall response rate 67%). Up to the 5-year follow-up none of the patients with complete response had recurrence or new lesion. In both studies the cosmetic results were excellent and the reported adverse events were mostly of mild intensity. ConclusionsThe use of the combination of IFN-alpha 2b and IFN-gamma showed efficacy in basal cell carcinoma and cutaneous squamous cell carcinoma promoting a long term response for at least 5 years and decreasing the rate of new lesions, safely and with excellent cosmetic effects.

Cancer cell lines are valuable models for studying tumor biology, yet their genomic evolution during culture can compromise experimental reproducibility. We conducted a detailed genomic analysis of the triple-negative breast cancer cell line MDA-MB-231, examining sublines obtained from different sources, at various time points, and across distinct passages. We introduce the concept of intraline heterogeneity (ILH) to highlight the genomic variability observed among these sublines. Our analyses revealed extensive genomic diversity, including differences in single nucleotide variants (SNVs) and copy number alterations (CNAs). In particular, CNAs exhibited remarkable heterogeneity, with pronounced chromosomal gains and losses between sublines, underscoring the impact of genomic instability on ILH. These findings suggest that ILH may influence experimental outcomes, emphasizing the importance of considering passage-specific genomic characterization to ensure consistency and reliability in cancer research.

Although cancer has been associated with COVID-19 risk and mortality in hospital-based studies, few population-based studies have been reported. Utilizing data from the UK Biobank (UKB), a population-based prospective cohort, we formally tested the association of over 44 different types of cancer with COVID-19 infection and mortality among 7,661 subjects who were tested by June 17, 2020. Compared to non-cancer subjects, cancer subjects (N=1,521) had significantly lower overall risk for COVID-19 infection [odds ratio (OR) and 95% confidence interval (CI): 0.79 (0.68-0.92), P=2.60E-03]. However, a trend of higher risk for COVID-19 mortality was found among 256 COVID-19 positive cancer patients, especially for hematologic cancers such as non-Hodgkin lymphoma [3.82 (1.17-12.01), P=0.02]. In cancer patients, while few demographic, lifestyle, genetic and comorbidity factors predicted risk for COVID-19 infection, older age, male sex, heart disease and hypertension significantly predicted COVID-19 mortality. The lower risk for COVID-19 infection is likely due to extra caution in COVID-19 prevention and more testing among cancer patients, an encouraging finding that demonstrates the feasibility of intervention. These results, if confirmed in future releases of UKB data and other independent populations, may provide guidance for COVID-19 prevention and treatment among cancer patients.

Human essentiality genes are significantly enriched in targeted therapies successfully used in oncology. Embedding human essentiality metrics into discovery pipelines could optimise the delivery of highly effective targeted therapies among clinical development strategies.

PurposegBRCA1/2 pathogenic variant (PV) carriers have elevated young-onset breast cancer risk. Understanding the distinct genomic landscapes of gBRCA1- and gBRCA2-associated breast cancer, including presence of PARP and CDK4/6 inhibitor (PARPi; CDK4/6i) response-associated alterations, may inform treatment selection for these patients. Patients and methodsWe evaluated 136 treatment-naive primary tumors from POSH study participants diagnosed with breast cancer before age 50 years (92.6% diagnosed [&le;]40): gBRCA1 86(63.2%), gBRCA2 50(36.8%). We evaluated somatic mutational and copy number variations (CNV), allele-specific loss of heterozygosity (asLOH), homologous recombination deficiency (HRD), and single-base substitution signatures (SBS) from whole exome sequencing. ResultsBoth gBRCA1 (93%) and gBRCA2 (96%) breast cancers had high rates of asLOH. We found significant differences between gBRCA1 and gBRCA2 tumors in average HRD scores (57.4{+/-}1.3 vs 43.7{+/-}1.5, p<0.0001) and SBS composition: SBS1 (aging-associated) 12.9 vs 7.3, p=0.013; SBS18 (reactive oxygen species [ROS]-associated) 1.4 vs 0, p=0.007; SBS3 (HRD-associated) 27.3 vs 42.6, p=0.002; and SBS26 (mismatch repair-associated) 5.9 vs 9.4, p=0.049. Compared to gBRCA2 tumors, gBRCA1 tumors with asLOH were significantly enriched for gains of chr6q, and alterations in Hallmark ROS, DNA repair, and epithelial-mesenchymal transition pathways. In ER-positive, HER2-negative tumors from POSH gBRCA1/2 carriers compared to noncarriers from the TCGA, we found significant enrichment of RB1 (OR:6.3, 95%CI:2.8-15.4, padj=0.001), TP53 (OR:4.6, 95%CI:1.9-12.1, padj=0.017), FAT1 (OR:3.9, 95%CI:1.84-8.7, padj=0.013), and MYC (OR:4.0, 95%CI:1.8-9.1, padj=0.017) SNV/indels/CNVs, which are associated with CDK4/6i resistance. ConclusionOur data suggest that PARPi may be preferable over CDK4/6i to treat ER-positive, HER2-negative breast cancer in young-onset gBRCA1/2-associated breast cancer when both therapies are considered in adjuvant and metastatic settings. Additionally, we identified significant differences between gBRCA1- and gBRCA2-associated tumors, which may inform therapeutic development.

BackgroundNumerous studies have shown that elderly women with endometrial cancer (EC) have a higher risk of recurrence and cancer-related death. It is, however, unclear whether aging is a causal prognostic factor, or whether other risk factors become increasingly common with age. We address to this with a unique multi-method study design using state of the art statistical and causal inference techniques on datasets of three large randomised trials. MethodsData of 1801 women participating in the randomised PORTEC-1, -2 and -3 trials were used for statistical analyses and causal inference. The cohort included 714 patients with intermediate-risk EC, 427 high-intermediate risk EC patients and 660 high-risk EC patients. Associations of age with clinicopathological and molecular features were analysed using non-parametric tests. Multivariable competing risk analyses were performed to determine the independent prognostic value of age. To analyse age as a causal prognostic variable a deep learning Causal Inference model called AutoCI was used. FindingsMedian follow-up was 12{middle dot}3 years for PORTEC-1, 10{middle dot}5 years for PORTEC-2 and 6{middle dot}1 years for PORTEC-3. Both overall recurrence and EC-specific deaths significantly increased with age. Moreover, elderly women had a higher incidence of deep myometrial invasion, serous tumour histology and p53abn tumours. Age was an independent risk factor for both overall recurrence (HR 1{middle dot}02 per year, 95%CI 1{middle dot}01-1{middle dot}04; p=0{middle dot}0012) and EC-specific death (HR 1{middle dot}03 per year, 95%CI 1{middle dot}01-1{middle dot}05; p=0{middle dot}0012), and was identified as a significant causal variable. InterpretationThis study shows that advanced age is associated with more aggressive tumour features, and independently and causally related to worse oncological outcomes. Therefore, treatment for endometrial cancer in elderly women should not be de-escalated based on their age alone. FundingThe PORTEC-1, -2 and -3 trials and the associated translational studies are supported by the Dutch Cancer Society.

Neoantigens are newly formed antigens generated by cancer cells but absent in normal cells. With their high specificity and immunogenicity characteristic, neoantigens are considered as an ideal target for immunotherapy. This study was aimed to investigate the signature of neoantigens in breast cancer. Somatic mutations, including SNVs and indels, were obtained from cBioPortal of 5991 breast cancer patients. For neoantigen prediction, 738 non-silent somatic variants present in at least 3 patients were selected., PIK3CA (38%), the highly mutated gene in breast cancer, can produce the highest number of neoantigens per gene. Some pan-cancer hotspot mutations, such as PIK3CA E545K (6.93%), can be recognized by at least one HLA molecule. Since there are more SNVs than indels in breast cancer, SNVs are the major source of neoantigens. Patients with hormone receptor positive or HER2 positive are more competent to produce neoantigens. Age, but not clinical stage, is a significant contributory factor of neoantigens production. We believe a detailed description of breast cancer neoantigens signatures could contribute to neoantigens based immunotherapy development.

BackgroundBreast cancer susceptibility gene testing (BCSG-testing) is expanding in relation to both eligibility for testing and number of genes included on testing panels. However, uncertainty remains regarding the most effective testing strategies for identifying clinically actionable germline pathogenic variants (gPVs) while balancing increased burden on breast and genetics clinical services. Patients and MethodsThe North Thames Mainstreaming of Breast Cancer Genetic Testing (NT-MBGT) programme piloted unselected breast cancer (BC) patient BCSG-testing via a clinician-light BRCA-DIRECT mainstreaming pathway. We present real-world evaluation of (i) gPV pick-up rates according to BC characteristics and (ii) operational feasibility, acceptability, and satisfaction with the BRCA-DIRECT expanded testing pathway. ResultsThe BRCA-DIRECT pathway successfully tested 3,517 newly-diagnosed BC patients within 14 National Health Service (NHS) breast oncology units, with high levels of patient and breast healthcare professional (HCP) satisfaction, and genetics HCPs reporting concomitant decrease in service referrals. The overall pick-up rate of gPVs was 4.7%. Current NHS eligibility criteria would have offered testing to 20.6% of patients and identified 49.2% of observed gPVs in high penetrance (HP)-BCSGs (BRCA1/BRCA2/PALB2) and 18.2% of gPVs in intermediate penetrance (IP)-BCSGs (CHEK2/ATM/RAD51C/RAD51D). Ultra-simple eligibility criteria could improve detection (sensitivity) to 74.6% and 61.4%, respectively, whilst increasing testing to 50.2% of BC cases. ConclusionsEvidence from the NT-MBGT programme demonstrates that expanding BCSG-testing via a clinician-light pathway is acceptable and feasible, without increasing the burden on limited breast and genetics workforce, and has high satisfaction. Simplified testing criteria could improve identification of gPVs in HP-BCSGs. The concomitant increased pick-up of gPVs in IP-BCSGs warrants further consideration. highlightsO_LIIn this real-world evaluation we observed the successful rollout of the BRCA-DIRECT streamlined, clinician-light mainstreaming pathway for a pilot of germline breast cancer susceptibility gene testing in 3517 unselected breast cancer patients from 14 regional breast oncology/surgical units. C_LIO_LIPatients undergoing testing via the pathway reported high levels of satisfaction and low decisional regret, with breast and genetics healthcare professionals highly recommending the pathway for mainstream testing. C_LIO_LIDifferences were observed between breast healthcare professionals preferring unselected breast cancer patient testing and genetics healthcare professionals preferring restriction to current national testing criteria due to broader concerns around equity of access to testing. C_LIO_LIWe identified that current national testing criteria would have missed identifying 50.8% of germline pathogenic variants in high-penetrance, clinically actionable genes, likely having implications for treatment and surgical decision-making in the breast cancer patients. C_LIO_LIWe evaluated the performance of two additional approaches for establishing testing eligibility criteria to understand how we could best balance maximising identification of germline pathogenic variants (sensitivity) whilst limiting (unnecessary) testing within the breast cancer patient population (specificity). C_LI

Background: Trastuzumab deruxtecan (T-DXd) is active in HER2-expressing solid tumours, but trials excluded HER2 immunohistochemistry (IHC) 1+ disease, and data in pretreated ovarian cancer are lacking. We evaluated real-world T-DXd activity and genomic correlates in pretreated ovarian cancer, predominantly high-grade serous (HGSOC). Methods: HER2 expression was assessed in an unselected ovarian cancer cohort (N=74). Fifteen patients receiving off-label T-DXd (14 HGSOC, 1 clear cell; IHC 1+ to 3+) had HER2 status centrally confirmed using gastric-type criteria. Activity was assessed by intra-patient growth modulation index (GMI; progression-free survival [PFS] on T-DXd divided by PFS on the prior line; [&ge;] 1.33 considered meaningful). Patients on treatment at data cut-off were censored. Objective response (RECIST 1.1) was assessed centrally where imaging was available (n=8). Results: Of the 40 HER2-expressing tumours, 15 received T-DXd, limited mainly by reimbursement. Among 14 evaluable patients (median 5 prior lines), 9 reached a GMI [&ge;] 1.33 (median 1.69); 8 remained on treatment at cut-off, making durability preliminary. Confirmed partial responses occurred across the HER2 spectrum. Benefit was independent of homologous-recombination (HR) status: one HR-proficient, CCNE1-wild-type patient achieved prolonged control and was rendered disease-free after radiotherapy to an oligoprogressive lesion. Exploratory analysis showed all four evaluable CCNE1-amplified tumours had reduced or non-durable benefit. Conclusions: T-DXd shows preliminary, clinically meaningful activity in HER2 IHC 1+ ovarian cancer independent of HR status. CCNE1 amplification may attenuate benefit, a candidate biomarker for WEE1-inhibitor combinations. Approval restricted to IHC 3+ disease would exclude most responders in this cohort. Prospective validation is required.

BackgroundApproximately half of ovarian high-grade serous carcinomas (HGSC) have homologous recombination deficiency (HRD). However, HRD is not well-characterized in Black individuals. ObjectiveTo characterize HGSC HRD by self-reported race and evaluate whether differences in HRD are associated with ovarian cancer mortality. Study populationCohort study using data collected from two population-based case-control studies of ovarian cancer. Cases were selected based on self-reported race (178 Black, 123 White) and pathologically-confirmed HGSC. ExposuresHRD features identified using matched tumor-normal whole-exome DNA sequencing and categorized as germline or somatic variants in homologous recombination pathway genes, or the SBS3 HRD-associated signature. OutcomesMedian difference and 95% confidence intervals (CI) for age at diagnosis and tumor mutation burden, and age and stage-adjusted hazard ratios (HR) and 95%CIs for survival, comparing individuals with an HRD feature to those without, separately by self-reported race. ResultsMore of the germline and somatic variants detected among Black individuals compared with White individuals were unannotated or variants of uncertain significance (VUS; germline 65% versus 45%; somatic 62% versus 50%, respectively). While the prevalences of many HRD features were similar between Black individuals and White individuals, Black individuals had a higher prevalence of the HRD signature identified using de novo mutational signature analysis (40% versus 29%) and germline BRCA2 variants (8% versus 2%) compared with White individuals. We observed that among Black individuals, BRCA2 variants were associated with better survival (somatic HR=0.23, 95%CI 0.07-0.76; germline HR=0.48, 95%CI 0.22-1.03), while germline BRCA1 variants were associated with worse survival (HR=2.11, 95%CI 1.14-3.88). When we restricted to VUS and unannotated variants, we observed similar associations with survival for BRCA2 among Black individuals (somatic HR=0.18, 95%CI 0.04-0.75; germline HR=0.40, 95%CI 0.15-1.09). Conclusions and RelevanceHRD testing informs precision-based medicine approaches that improve outcomes, but a higher proportion of VUS among Black individuals may complicate referral for such care. Our findings emphasize the importance of recruiting diverse individuals in genomics research and better characterizing VUS.

BackgroundA common germline deletion polymorphism in the APOBEC3B gene increases the rate of somatic hypermutation in breast cancer, which in turn is associated with greater neoantigen burden and immune activation. This phase II study evaluated the impact of the APOBEC3B deletion polymorphism on the response to pembrolizumab monotherapy in metastatic HER2-negative breast cancer patients. Patients and methodsEligible patients had a confirmed diagnosis of metastatic HER2-negative breast cancer, 1-3 prior lines of therapy, and documented homozygous or heterozygous germline deletion of APOBEC3B. Patients received 200 mg of pembrolizumab intravenously every 3 weeks for up to 2 years. The primary endpoint was objective response rate. Secondary endpoints were disease control rate, progression-free survival, and overall survival. ResultsAll enrolled patients (N = 44) were women, 36% had PD-L1-positive tumours, and 62% had received [&ge;]2 previous lines of therapy for metastatic disease. ORR (95% CI) was 20.5% (9.8 - 35.5) in the total and 30.0% (6.7 - 65.3) in the PD-L1-positive populations. Disease control rate (95% CI) was 52.3% (36.7 - 67.5) and 40% (12.2 - 73.8), respectively. Median PFS was 3.1 months (95% CI, 2.1 - 4.3), and 6-month PFS rate was 29.5% (95% CI, 18.7 - 46.6). Median OS was 15.2 months (95% CI, 11.7 - 26.5), and 12-month OS rate was 60.2% (95% CI, 46.5 - 77.7). Treatment-related adverse events occurred in 30 (68.2%) patients, including 1 (2.3%) with grade 3 AE. There were no deaths due to AEs. ConclusionsPembrolizumab monotherapy demonstrated durable antitumour activity in a subset of previously treated metastatic HER2-breast cancer patients with germline APOBEC3B deletion. Clinical trial registrationClinicalTrials.gov, NCT03989089.

BackgroundTargeted therapies have transformed breast cancer management by focusing on molecular drivers such as HER2 amplification, hormone receptor signaling, and CDK4/6 pathways. They aim to increase disease control while reducing systemic toxicity compared to conventional chemotherapy. ObjectiveThis review assessed the effectiveness and safety of targeted therapies in advanced and metastatic breast cancer, with progression-free survival (PFS) as the primary outcome and overall survival (OS), objective response rate (ORR), and safety as secondary endpoints. MethodsA systematic search of PubMed/MEDLINE and the Cochrane Library was conducted between January 2015 to March 2025 for randomized controlled trials and large clinical studies comparing conventional and targeted pharmacotherapy in breast cancer. Eligible studies reporting progression-free survival were included. PRISMA guidelines were strictly followed. Data extraction and risk-of-bias assessments were performed independently by two reviewers. ResultsFifteen trials with more than 10,000 patients were included. In HER2-positive disease, trastuzumab deruxtecan (T-DXd) significantly improved PFS and OS compared with trastuzumab emtansine, while tucatinib combinations provided strong intracranial control. CDK4/6 inhibitors (ribociclib, palbociclib, abemaciclib) consistently extended PFS in HR+/HER2-populations across pre- and postmenopausal groups. For triple-negative breast cancer, atezolizumab plus nab-paclitaxel improved outcomes in PD-L1-positive patients. Safety profiles were distinct, with interstitial lung disease from T-DXd, hematologic toxicity from CDK4/6 inhibitors, and immune-related events with checkpoint inhibitors. ConclusionsTargeted therapies substantially improve PFS, with OS benefits in several trials, setting new standards across breast cancer subtypes. Balancing efficacy with toxicity management and improving global access remain essential to maximize clinical benefit.