Citations

Abstract Background Women with a pathogenic variant in BRCA1 or BRCA2 are at high risk of developing ovarian cancer, and it is often recommended that they undergo bilateral salpingo-oophorectomy at an early age, resulting in surgical menopause. Menopausal hormone replacement therapy (HRT) is an effective way to mitigate the adverse outcomes of early menopause; however, the safety of menopausal HRT on breast cancer risk in this population has not been established. Methods We conducted a prospective matched analysis of HRT use following menopause and breast cancer risk in BRCA carriers. Women who initiated HRT were matched one-to-one with women who had not initiated menopausal HRT by gene, year of birth, and age at menopause, resulting in 676 matched pairs. Menopausal HRT use collected by questionnaire included formulation and mode of administration. Results After a mean of 5.6 years, there were 87 (12.9%) incident breast cancer cases in the 676 exposed women and 128 (18.9%) cases in the 676 unexposed women (P = .002). Compared with unexposed matched control individuals, women who used estrogen alone experienced a statistically significantly decreased risk of breast cancer (hazard ratio = 0.37, 95% CI = 0.24 to 0.57). No protective or adverse effect was associated with the use of estrogen plus progestogen (hazard ratio = 0.94, 95% CI = 0.54 to 1.63). Conclusions Our findings suggest no substantial increase in the risk of breast cancer in BRCA carriers with the use of HRT and that estrogen alone might be protective.

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature, and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and Appendix 2 (online only) for more. PURPOSE To provide guidance on the recommended management of cancer in pregnant patients. METHODS A multidisciplinary Expert Panel convened and conducted a systematic review of the literature. RESULTS The systematic review identified 450 eligible studies. Much of the evidence consisted of observational data, case series, and case reports. RECOMMENDATIONS Management of cancer during pregnancy should be grounded in a values-based informed-consent process outlining maternal and fetal risks and anticipated benefits. Diagnostic evaluation should follow the as low as reasonably achievable (ALARA) principle, with timing of diagnostic studies individualized based on urgency of cancer detection, potential dangers of delay, and the balance of risks to both the pregnant patient and her embryo or fetus. Due to significant risk of harm to the developing embryo and/or fetus, systemic therapy should be deferred until the second trimester. Methotrexate, hormonal therapies, human epidermal growth factor receptor 2–targeted agents, vascular endothelial growth factor and poly (ADP-ribose) polymerase inhibitors, antibody-drug conjugates, and all cellular therapies are contraindicated during pregnancy, regardless of gestational age. For patients who wish to continue their pregnancy, delivery should be planned at or after 37 weeks, with the final chemotherapy dose scheduled 2-4 weeks before birth. Referral to psychosocial support services is essential to address emotional and practical challenges, reduce distress, and support shared decision making. Additional information is available at www.asco.org/survivorship-guidelines .

Background. Liver transplantation (LT) remains the most effective treatment for patients with hepatocellular carcinoma (HCC), offering 5-y recurrence rates as low as 15%. Recent advances in organ preservation, particularly hypothermic oxygenated machine perfusion (HOPE), have demonstrated the ability to attenuate ischemia–reperfusion injury (IRI). However, whether HOPE can reduce HCC recurrence rates by mitigating IRI remains an open question. In this study, we aimed to compare oncological outcomes after LT for HCC with and without the use of HOPE. Methods. We conducted a retrospective cohort study including 137 patients who underwent LT for HCC with grafts from donation after brain death. Risk factors for HCC recurrence were analyzed using Cox regression. To assess the impact of HOPE on oncological outcomes, propensity score matching was used to adjust for baseline differences. Results. Cox regression identified Milan Criteria status as a significant predictor of HCC recurrence. Among the 32 patients in the HOPE group, no HCC recurrence was observed over a median follow-up of 2.11 y. In contrast, within the control group of 105 patients, 8 (7.6%) experienced recurrence within 2 y posttransplantation. Although this translated into a significant difference in time-to-recurrence after propensity score matching, recurrence-free survival and overall survival did not differ significantly. Conclusions. Our findings suggest that HOPE treatment of donation after brain death liver grafts may reduce early HCC recurrence after LT. Although only nonsignificant trends were observed in recurrence-free survival and overall survival within the first 2 y posttransplant, these results underscore the potential of HOPE to influence oncological outcomes. Long-term follow-up, prospective randomized controlled trials, and basic research are warranted to further elucidate the role of HOPE and IRI.

Abstract Introduction Penile implant (PI) surgery is a well-recognized strategy for erectile dysfunction (ED) with excellent functional/satisfaction outcomes. To date, little attention has been paid to the attitudes and satisfaction outcomes of female partners of such patients. Objective To qualitatively assess how female partners feel about PI surgery to inform the development of a female partner specific questionnaire. Methods Female partners of men who had undergone PI surgery (3-piece inflatable) underwent concept elicitation interviews. Prior to this, a panel of experts in female sexual health and PI surgery was convened to define potential domains of interest. Women were interviewed by one of two female sexual medicine clinicians to elicit concepts. As part of the spontaneous item generation phase, participants were asked about their attitudes, hopes and concerns prior to PI surgery, as well as changes in partner post-surgery. Participants were then asked whether they identified domains raised by the expert panel that were not mentioned during the spontaneous phase. Additional open-ended questions were asked about experiences before and after PI surgery. Interviews were transcribed verbatim for subsequent qualitative analysis by 2 trained members of the study team. Results 12 women have been interviewed. Mean partner age = 60 years, relationship duration = 20 years. Interviews were held <12 months post-PI for 17% of partners, 12-24 months for 25%, >24 months for 58%. Partner communication and involvement in decision to get the implant were uniquely raised as pre-surgical concerns, whereas PI attributes were uniquely mentioned as post-surgical concerns. How the PI has impacted the man’s self-esteem, whether impacts to self-esteem have affected the partner, and overall satisfaction with sex were most common concepts raised across pre- and post-surgery (See Table). Conclusions Using rigorous qualitative methodology, we have identified concepts that are unique to pre-surgery, post-surgery, and common across the surgical experience among partners of men who have undergone penile implant surgery. These data will facilitate development of a tool to assess female partner attitudes, beliefs and satisfaction prior to and after PI surgery. Disclosure No

OBJECTIVE Achieving submillimetric accuracy in stereotactic neurosurgery remains critical for safely targeting deep brain structures. Current workflows rely on intraoperative CT to register stereotactic frames to preoperative imaging, but this introduces additional radiation exposure, cost, and workflow complexity. Three-dimensional surface scanning (3DSS) potentially offers a fast radiation-free alternative capable of capturing detailed craniofacial anatomy and frame geometry. Therefore, the aim of this cadaveric study was to evaluate the feasibility, accuracy, and navigational compatibility of integrating 3DSS into stereotactic workflows as a potential replacement for intraoperative CT. METHODS A human cadaveric head was imaged with both thin-slice CT and structured-light 3DSS after mounting stereotactic frame components. CT, 3DSS, and computer-aided design (CAD) models were registered using a multistep point cloud alignment pipeline involving the fast point feature histogram, the random sample consensus method, and the iterative closest point algorithm. Accuracy was assessed using surface deviation error, root mean square error (RMSE), and fiducial registration error within a commercial neuronavigation platform. RESULTS Fusion of the 3D facial scan with CT provided a mean surface deviation error of approximately 0.4 mm. Registration of the 3DSS-derived N-bar localizer to its CAD reference model produced a frame alignment RMSE of 1.3 mm. Within the navigation system, the 3DSS-based workflow achieved a mean fiducial registration error of 0.14 mm (range 0.02–0.20 mm), outperforming the conventional CT-based method (mean error 0.20 mm, range 0.09–0.40 mm). CONCLUSIONS The 3DSS-based method enabled precise submillimetric stereotactic registration without the need for intraoperative CT, reducing radiation exposure and operative complexity. This workflow is fully compatible with existing navigation systems and could serve as a practical radiation-free alternative in stereotactic neurosurgery. Future work will focus on automating frame detection, incorporating artificial intelligence–driven fusion methods, and validating this approach in live surgical settings.

ABSTRACT The standard treatment for Haemophilia B (HB) involves frequent intravenous (IV) infusions of recombinant factor IX (FIX), which imposes a significant financial burden on patients. FIX delivery as messenger RNA using lipid nanoparticles (LNPs) presents a promising alternative, but achieving prolonged and effective protein expression remains challenging. To this end, we developed Galactosylated Lipid Nucleic Acid complex (GaLiNAx) to enhance the delivery of chemically modified FIX mRNAs. The nanocarrier encompasses an ionizable galactosylated lipid to enable receptor‐mediated endocytosis and a transfection‐competent cationic lipid for optimal mRNA complexation. We incorporated truncated albumin UTRs and base modifications in functional FIX mRNA to enhance hepatic translation. In an HB mouse model, GaLiNAx demonstrated therapeutically relevant FIX protein expression for about one month after single dose offering a cost‐effective option. Safety assessments indicated that multiple doses of GaLiNAx could be administered without toxicity to any major organs. These results highlight the potential of long‐lasting mRNA therapy as an effective protein replacement strategy for HB, paving the way for future mRNA therapeutics targeting other monogenic liver disorders.

Abstract Chimeric Antigen Receptor (CAR) T cell therapy is a transformative treatment for hematologic malignancies. However, ex vivo autologous CAR T cell manufacturing presents substantial logistical and clinical challenges. Direct in vivo CAR-T cell engineering offers a new paradigm for CAR T delivery. We recently developed the CD3-targeted lentiviral vector LV-169 which can deliver a CAR transgene to resting niche-resident T cells in lymphoid tissues. LV169 is pseudotyped with a mix of chimeric and nonchimeric VSV-G proteins detargeted (blinded) from the natural LDL receptor and re-targeted to T cells through the display of a CD3-specific scFv. Here we demonstrate that LV169 can specifically deliver a functional aBCMA-CAR transgene to resting human T cells in PBMC cultures from the healthy volunteers and from multiple myeloma patients. For clinical translation, we selected an αBCMA-CAR construct comprising a fully human single heavy chain nanobody linked to 41BB and CD3z cytoplasmic signaling domains. Human T cells expressing this CAR construct have low tonic signaling and efficiently kill BCMA-positive myeloma target cells with similar or lower associated cytokine release compared to a clinically relevant benchmark BCMA-CAR. To further improve LV169 and to minimize CAR protein incorporation in the LV envelope which may lead undesirably to myeloma cell transduction, we placed the CAR transgene under a T-cell specific Lck promoter in reverse orientation relative to the 5' LTR. The transcriptional activity of the Lck promoter was comparable to that of a constitutive EF1a promoter in primary T cells and, in contrast to EF1a had minimal activity in a variety of other tested cell types including the HEK293T producer cell line and the THP-1 monocytic cell line. Western blotting confirmed the absence of CAR protein in LV particles (LVP) generated using the Lck promoter-driven reverse orientation construct. In contrast, high levels of CAR protein were detected in LVP generated using the parental EF1a promoter-driven construct. The LV-incorporated CAR protein mediated off-target gene delivery to BCMA-positive myeloma cells. The therapeutic efficacy of intravenously administered LV169 LV particles carrying BCMA-CAR constructs was tested in the OPM-2 human multiple myeloma xenograft model. NSG mice with knockout of MHC-I and MHC-II, and with advanced disseminated OPM-2-Luc tumors were engrafted with human PBMC one week prior to intravenous LV169-BCMA-CAR administration. Mice were treated with single intravenous injection of LV169 at different doses 3 weeks after tumor engraftment. OPM-2-Luc tumor burden was monitored by regular luciferase imaging. All treated mice cleared their tumors within 28-days following LV administration and the rate of clearance was correlated to the LV particle dose. Even at the 4e8 dose level (by p24) tumors were completely cleared. Eighty four days post-treatment the treated mice remained tumor-free and resisted re-challenge with OPM-2 tumor cells. Circulating CAR-T cells, monitored by flow cytometry, became detectable by 14 dpi and peaked between 21-35 dpi. Following tumor clearance, the number of circulating CAR-T cells declined dramatically. The treatment was well tolerated and analysis of cytokines associated with CAR-T cell cytotoxicity confirmed the absence of a severe cytokine storm. IFNγ was the only cytokine which was elevated during the expansion period of CAR-T cells, while IL-2, IL-6, TNFα and GM-CSF were barely detectable. In summary the characteristics of our new developed LV169-based platform make it suitable for further clinical translation which is underway.

Abstract Direct in vivo T cell engineering offers a new paradigm for CAR T delivery. We have evaluated several approaches to engineer lentiviral (LV) vectors capable of delivering CAR transgenes directly and selectively to T cells in vivo, within the lymphoid niche. Our goal was to develop an LV delivery platform that following intravenous administration can selectively bind and activate T cells, deliver and integrate the (CAR) transgene into genomic DNA, and drive CAR expression on the T cell surface. Further requirements were that the retargeted LV should be associated with minimal off-target transduction of tumor cells and normal host tissues and should be manufacturable at titers sufficient for human application. Our strategy for retargeting has been to modify the trimeric VSV-G protein, which is well established for efficient LV pseudotyping. Of the approaches evaluated, three retargeting platforms have proven to be effective: direct covalent display, indirect covalent display, and G-capping. Direct covalent display. This (LV-169) approach uses chimeric VSV-G protein that contains a CD3-targeting ligand displayed as a N-terminal extension of VSV-G protein that has been mutated to ablate (blind) its interaction with the LDL receptor. Chimeric and nonchimeric blinded G proteins are co- incorporated into LV particles within mixed envelopes which bind to CD3. Upon binding to cell surface CD3, the engineered particles activate T-cells and enter acidifying endosomes, whereupon they trigger membrane fusion and deliver their payloads. LV-169 displaying an anti-human CD3 scFv selectively transduced resting human T cells in PBMC cultures, in fresh human whole blood and following intravenous administration to humanized mice. In immunocompetent Cre reporter mice, surrogate vectors displaying anti-murine CD3 scFv selectively transduced lymph node resident T cells, with off-target transduction being limited to tissue-resident macrophages. To eliminate the incorporation of CAR protein into the LV-169 envelope, which can lead to highly undesirable transduction of tumor cells expressing the CAR target, we placed the CAR transgene in reverse to 5'LTR orientation, downstream of a T-cell specific promoter/enhancer. In vivo efficacy of LV-169-BCMA-CAR was demonstrated in humanized mice bearing disseminated OPM-2 myeloma tumors. Clinical translation of this construct is now underway. Indirect covalent display. In this G-protein engineering approach, a short peptide (SPY-tag) is displayed as an N-terminal extension of the LDLR-blinded VSV-G protein. The SPY-tagged LV vectors are then covalently modified to display a CD3-targeting ligand by simply mixing them at room temperature with a bifunctional fusion protein consisting of the SPY-catcher and the CD3 ligand. Under these conditions, the SPY-catcher and the SPY-tag spontaneously form a covalent isopeptide bond. The CD3 ligand-modified LV particles were shown to specifically activate and transduce T cells ex vivo within human PBMC cultures. G-capping. In the final approach, the VSV-G protein is not genetically modified. Instead, a “capping” protein crosslinker that binds directly to the unmodified G protein on preformed LV particles is used to mask their LDLR binding sites and redirect them to interact with CD3. Mixing of the CD3-targeted capping protein with traditional G-pseudotyped LV particles leads to efficient binding of the cap to the trimeric G proteins. The cap-modified LV are unable to interact with LDLR but interact efficiently with CD3. CD3-capped LV particles were highly specific and efficient in human T cell activation and transduction in PBMC cultures. The association between the G protein and the bound cap is highly stable during freeze-thaw cycles and at room temperature, a critical attribute of this platform to facilitate the manufacture of a clinically and commercially viable LV product. In summary, we have developed three translationally relevant platform technologies for the generation of LV particles capable of delivering CAR transgenes specifically and efficiently to resting niche-resident T cells after intravenous administration. Manufacturing studies are underway and, in the case of the LV-169 platform, clinical translation is already in progress.

Abstract Introduction: Cilta-cel is a BCMA-directed CAR T-cell therapy that has shown remarkable efficacy in patients with RRMM. As real-world (RW) experience with cilta-cel continues to expand, and with the recent FDA guidance reducing the recommended proximity to the CAR T center from four to two weeks post-infusion, there is growing interest in identifying patients at low risk for severe early complications who may be safely managed in the outpatient setting and potentially ‘discharged’ home earlier. Methods Data were collected from 769 patients with RRMM treated with cilta-cel at 15 institutions in the U.S. via the Multiple Myeloma Immunotherapy Consortium.Logistic regression was used to identify predictors of patients who could be managed in the outpatient setting (low-risk group). Based on expert consensus within the Consortium, low-risk patients were defined as: grade ≤1 CRS, no ICANS, and no IEC-HS. The remaining patients were categorized as high-risk. We evaluated baseline characteristics with missingness < 20% as predictors, including age, sex, race, and ethnicity, ECOG performance status (PS) at time of lymphodepletion (LD), extramedullary disease, bone marrow plasma cell (BMPC) percentage, high-risk cytogenetics, bridging therapy including response, penta-refractory status, number of prior lines of therapy, prior anti-BCMA therapy, baseline C-reactive protein (CRP), and baseline ferritin. The cohort was restricted to patients with complete data on all predictors (n=455) and split into a training and testing cohort (80/20 split, n=364/91). Bidirectional stepwise regression was used to build the predictive model using variables with significance of p<0.15 selected for entry. The best model was selected based on the AIC (Akaike Information Criterion) and a significance level of p<0.05. Results Among the 455 patients with complete data included in the final model, 290 (64%) were categorized as low-risk and 165 (36%) as high-risk. Compared to the low-risk group, high-risk patients were more likely to have an ECOG PS ≥2 at time of LD (20% vs 9%, p<0.001), high-risk cytogenetics (47% vs 35%, p=0.009), and penta-refractory disease status (34% vs 24%, p=0.031). High-risk patients also had a higher median BMPC percentage (15% vs 5%, p<0.001), and higher baseline pre-LD CRP and ferritin. Overall response rates were high, at 95% vs 90% (p=0.047) for the low vs high risk groups, with complete response or better achieved in 73% vs 66% of patients, respectively (p=0.14). With a median follow-up of approximately 11 months, median progression-free survival was not reached (95% CI: 27-NA) in the low-risk group and 18.2 months (95% CI: 13.1-NA) in the high-risk group. In terms of safety, non-ICANS neurotoxicity (NINT) occurred less frequently in the low-risk group (6.6% vs 13%, p=0.015). Specifically, Parkinsonism was observed in 1.7% vs 6.1% (p=0.013), and cranial nerve palsy in 4.5% vs 5.5% (p=0.7), respectively. Non-relapse mortality (NRM) was lower in the low-risk group (4.2%) compared to the high-risk group (14%; p < 0.001). The most common causes of NRM in the low- and high-risk groups were acute toxicities (0% vs 36%, including CRS, IEC-HS, and ICANS), delayed toxicities (0% vs 8%, including colitis, NINT, and Parkinsonism), infections (50% vs 48%), and other unrelated causes (50% vs 8%). The best model to predict low-risk patients that could be managed in the outpatient settingincluded BMPC percentage and ECOG PS at LD. In the training cohort, patients with a higher pre-LD BMPC percentage and an ECOG PS ³2 were less likely to be in the low-risk group(OR per 1-unit change in BMPC percentage = 0.99, 95% CI=0.98-0.99, p<0.001 and OR for ECOG PS 2-4 = 0.38, 95% CI=0.20-0.72, p=0.003). The AUC for this model was 0.663 in the training cohort and 0.659 in the testing cohort. Conclusion In this large, multi-institutional cohort of patients with RRMM treated with cilta-cel, we identified clinical factors associated with lower risk for early severe toxicities, supporting outpatient administration and the potential for earlier discharge in selected patients, particularly those who are fit and have low disease burden. Our findings provide a practical framework to guide risk stratification and outpatient CAR T management strategies, particularly in light of evolving regulatory guidance and growing RW experience with cilta-cel.