Aneuploidy is near-ubiquitous in cancer and contributes to tumor biology. However, the temporal evolutionary dynamics that select for aneuploidy remain uncharacterized. We performed longitudinal genomic analysis of 755 samples from 167 patients with colorectal-derived neoplasias from different stages through metastasis and treatment. Adenomas had few copy number alterations (CNA) and most were subclonal, whereas cancers had many clonal CNAs, suggesting that progression goes through a CNA bottleneck. Individual colorectal cancer glands from the same tumor had similar karyotypes, despite evidence of ongoing instability at the cell level. CNAs in metastatic lesions, after therapy, and in late recurrences were similar to the primary. Mathematical modeling indicated that these data are consistent with the action of negative selection on CNAs that "trap" cancer genomes on a fitness peak characterized by specific CNAs. Hence, progression to colorectal cancer requires traversing a rugged fitness landscape, whereas subsequent CNA evolution is constrained by negative selection. SIGNIFICANCE:We profiled 167 long-term responders longitudinally (755 samples), documenting long-term cancer evolution. We found that a genetic bottleneck is required for progression and is associated with dramatic increase in CNAs but decrease in clonal diversity. After initiation, copy number evolution is constrained by negative selection through metastasis and treatment. See related commentary by Okada et al., p. 192.

Background The number of transmasculine and gender diverse (TMGD) individuals who retain their uterus or postpone surgery while using testosterone is increasing. However, the influence of exogenous testosterone on the risk of cervical cancer remains unclear. This study aims to assess the risk of cervical cancer and intraepithelial neoplasia in TMGD individuals undergoing testosterone treatment. Methods This retrospective, cohort study was conducted at the Amsterdam University Medical Centre in the Netherlands, included transmasculine and gender diverse (TMGD) individuals receiving testosterone at our clinic between February 17, 1972 and December 3, 2018. Data from medical records were linked to the national pathology database to acquire diagnoses related to cervical cancer or cervical intraepithelial neoplasia (CIN). Individuals assigned female at birth who received testosterone were included, excluding those last seen before 1991. Lesions >= CIN2 were classified as "high grade", considering their increased cancer progression risk. Based on observed and expected cases, age-adjusted standardised incidence ratios (SIR) were calculated to assess relative risk compared to cisgender women. Findings The cohort comprised 2095 TMGD individuals; 1200 participants underwent hysterectomy, and cervical biopsies obtained from seven patients. Median testosterone exposure time was 1.7 years (IQR 1.3-2.5). No cervical cancer cases were observed (0.30 (95% CI 0-1.4) expected). Five cases of >= CIN2 (0.002%) were observed, versus 9.5 expected (SIR 0.53 (95% CI 0.19-1.17). Interpretation In this large cohort with several years of testosterone exposure we did not observe any cervical cancer, nor did we observe an increased risk of >= CIN2. These findings should be interpreted with caution, as the relatively short median time of follow-up and lack of data on HPV infection prevalence and cervical screening may introduce bias. Longer follow-up studies incorporating this information are needed.

Locally advanced esophageal adenocarcinoma remains difficult to treat and the ecological and evolutionary dynamics responsible for resistance and recurrence are incompletely understood. Here, we performed longitudinal multiomic analysis of patients with esophageal adenocarcinoma in the MEMORI trial. Multi-region multi-timepoint whole-exome and paired transcriptome sequencing was performed on 27 patients before, during and after neoadjuvant treatment. We found major transcriptomic changes during treatment with upregulation of immune, stromal and oncogenic pathways. Genetic data revealed that clonal sweeps through treatment were rare. Imaging mass cytometry and T cell receptor sequencing revealed remodeling of the tumor microenvironment during treatment. The presence of genetic immune escape, a less-cytotoxic T cell phenotype and a lack of clonal T cell expansions were linked to poor treatment response. In summary, there were widespread transcriptional and environmental changes through treatment, with limited clonal replacement, suggestive of phenotypic plasticity.

The overall incidence of late-onset colorectal cancer (LOCRC, ≥50 years old) has decreased. However, the rates of early-onset colorectal cancer (EOCRC, <50 years old) have steadily increased, posing a major public health concern as EOCRC patients typically have poorer clinical outcomes. Sex-specific factors, including hormones and metabolites, have been underexplored as potential therapeutic targets for EOCRC. We propose that male and female EOCRC patients exhibit different metabolic responses in their colorectal tumors, which could have significant implications for personalized treatment approaches. We conducted a comprehensive metabolomics analysis on surgically resected colorectal tumors and matched adjacent normal mucosa from EOCRC and LOCRC patients (n=372). Disease-specific survival analysis was performed for individual patients. To determine the influence of sex and metabolite abundance on tumor progression, we employed multivariate Cox proportional hazard and early-late index models. We further validated the clinical significance of our findings using independent datasets from the NCBI Gene Expression Omnibus (n=582 patients), and a retrospective validation cohort from the SEER database (n=79506 EOCRC patients). Our discovery and validation cohorts revealed that male patients had significantly worse disease-specific survival in EOCRC. Metabolomic analysis revealed distinct metabolic sub-phenotypes influenced by sex. Younger male patients exhibited worse disease-specific survival compared to LOCRC, even after adjusting for the stage of CRC. Tumors from younger male patients showed enhanced amino acid utilization, characterized by increased asparagine and tryptophan metabolism, and increased fatty acid uptake to fuel growth. Independent validation revealed that high asparagine synthetase (ASNS) expression correlated with age in male EOCRC patients only. Modulating sex-biased tumor metabolomes may represent a potentially effective targeted strategy for the prevention and treatment of EOCRC in both men and women. Oladimeji Aladelokun, Abhishek Jain, Xinyi Shen, Samuel Butensky, Shiying Xiao, Allison Janak, Domenica Berardi, Carol Yang, Reza Aalizadeh, Sunny Siddique, Xiaomei Ma, Philip Paty, Rolando Garcia-Milian, Alison Berner, Jatin Roper, Sajid Khan, Caroline Johnson. Novel Sex-Specific Metabolic Phenotypes in Early Onset Colorectal Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr C001.

e13676 Background: Gender-diverse individuals identify their gender as different to the sex they were assigned at birth. This population experiences health inequity throughout the cancer care pathway partly stemming from limited access to specialist knowledge of gender-affirming care and its intersections with cancer. Notable issues include safety of gender affirming hormones, mutual implications of gender affirming surgeries with cancer surgeries and radiotherapy, and psychological support when dysphoria is exacerbated by a cancer diagnosis. Methods: In response, we established the UK Cancer and Transition Service (UCATS), a national virtual monthly multidisciplinary meeting (MDM) and clinic. Patients are eligible for referral if they identify as gender-diverse and have active or historical malignancy. The service was coproduced with patient and public involvement, including input from a specialist cancer charity for gender and sexual minority people. The service launched in June 2022 and began advertising and requesting patient feedback from January 2023. Results: Between June 2023 and January 2024 UCATS received 20 referrals (10 from gender services, 5 from oncology, and 5 self-referrals). Patients were aged 18 - 68 years. The most common tumour types were breast (n = 6), prostate (n = 5), and gastrointestinal (n = 3). Others were haematological, testicular, gynaecological, and central nervous system. One patient had a familial cancer syndrome, not active cancer. Patients were offered a virtual clinic appointment and MDM discussion. Reasons for referral included safety of gender affirming hormones and surgeries, and expedited gender consultations in view of prognosis, or need for cancer treatments that may affect gender-affirming care. Two patients did not attend, with one sending a nominated family member. Six patients had at least one external clinician dial in for the appointment. Seven patients received follow-up appointments. There were nine completed feedback forms, 4 after first appointment and 5 after follow-up. All patients rated both the communication at the appointment and the information given as 5/5. All patients rated their likelihood to recommend the service as 4 or 5/5. Other points of positive feedback were the detailed outcome letter, speed of appointment, and a sense of advocacy. Next steps include routine follow-up appointments (in response to feedback), wider advertising, increased frequency, and recruitment of nursing support. Conclusions: UCATS successfully caters to an unmet need, coordinating cancer and gender affirming care for gender diverse patients, and providing specialist knowledge and support for patients and care teams.

Abstract PISCA, originally introduced by Martinez et al. in 2018, represents a pivotal Bayesian phylogenetics tool for the modeling of tumor evolution using multi-region somatic chromosomal alteration (SCA) data. PISCA takes allele-specific copy number data, typically obtained from deep genome sequencing or SNP arrays, or absolute copy number data from low-pass genome sequencing methodologies. It extends the classic BEAST1 framework and inherits a rich repertoire of evolutionary models. Importantly, PISCA leverages longitudinal sampling to estimate SCA mutational clock rates, either employing strict clock models, where mutation rates remain constant throughout the evolutionary tree, or relaxed clocks, which allow each branch or subtree to possess its distinct mutation rate. This nuanced approach empowers PISCA to account for the heterogeneous rates of mutations, a pivotal consideration in understanding tumor evolution dynamics. However, PISCA has historically posed a formidable entry barrier for wider community adoption due to platform and Java dependencies for installation, as well as the need for manual or custom-scripted XML file generation. Here we showcase PISCA-box, a user-friendly interface designed to streamline the generation and testing of XML files. Our PISCA-box Docker image works on any desktop machine to create a locally hosted webpage, where users can input SCA data, sampling dates, select clock and demographic models, and set priors for key parameters - similar to the BEAST XML generator, BEAUTi. The Docker or Singularity installation can then be used for longer analyses using high-performance computing resources. To demonstrate its practical utility, we present novel colorectal cancer data. First, we examine data from a patient with a long-standing history of inflammatory bowel disorder (IBD), a known high-risk factor for colorectal cancer. This patient had undergone surveillance colonoscopies for many years, which provided 38 samples, and subsequently an additional 118 samples were collected from a total colectomy. All were analyzed with low-coverage whole genome sequencing. We find some samples from surveillance and colectomy form lineages with overlapping copy number events, that we used to construct a phylogeny, finding a cancer-adjacent clade that appears to evolve rapidly. A second dataset of multi-region samples from a cohort of exceptional survivors of oligometastatic colorectal cancer who lived >60 months from metastatic diagnosis with biopsies/resections across 3-10 time points is examined and temporal models are used to estimate the ages of metastatic clades. PISCA therefore harnesses the power of longitudinal SCA data to enable a comprehensive study of SCA dynamics. We are currently expanding this framework to include fluctuating methylation clocks which PISCA-box will soon include. By providing this accessible tool, we enable researchers to readily apply Bayesian phylogenetics to real-world clinical datasets to better understand tumor evolution. Citation Format: Heather E. Grant, Rachel Alcraft, Pablo Bousquets-Muñoz, Calum Gabbutt, Alison Berner, Mehmet Yalchin, Carlo C. Maley, Trevor A. Graham, Diego Mallo. PISCA-box: A user-friendly interface for Phylogenetic Inference using Somatic Chromosomal Alterations (PISCA) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B004.

There is evidence that gender-affirming hormone treatment (GAHT) for transgender individuals modulates their risk for specific malignancies including breast and prostate cancer, and meningiomas. However, there is insufficient data to make precise risk estimates accounting for age and inherited cancer risk. As such, screening recommendations remain broad. Even less evidence exists for best practice in the management of active or historical cancers in the transgender population. Guidance is therefore mainly extrapolated from cisgender populations but with considerations of the significant benefits of GAHT in the face of any hormonal risk. Clinical experience, the multidisciplinary team and shared decision making with the patient are vital in providing person-centred care, while further research is acquired.

Abstract A major challenge for inhibiting metastasis is the ability of cancer cells to reversibly switch states in response to microenvironmental cues along the metastatic cascade. The regulatory factors and signals from the microenvironment enabling colorectal cancer (CRC) cells to transition into an invasive state and to establish metastasis in the liver remain unknown. Using a combination of single-cell multiomics and spatial transcriptomics data from primary and metastatic CRC patients, we reveal putative metastasis-initiating cancer states with regenerative and inflammatory signatures, driven by transcription factors AP-1, NF-κB and YAP. We demonstrate the existence of an intermediate population with a hybrid regenerative and stem phenotype, indicating phenotypic transitions between stem and pro-metastatic cells. Our spatial analyses show localisation of the regenerative states at the invasive edge in primary CRC and in an immunosuppressive niche in liver metastasis, surrounded by immune and stromal cells that sustain these cells. We uncover putative ligand-receptor interactions driven by cancer-associated fibroblasts (CAFs), macrophages and CD8 T cells that activate the regenerative and inflammatory invasive phenotype in cancer cells. Together, our findings reveal regulatory and signalling factors that can be targeted to restrict transition into invasive states to impair metastasis.

Introduction Persistent infection with high-risk human papillomavirus (HPV) is the causal agent of several cancers including cervical, anal and oropharyngeal cancer. Transgender men and transmasculine non-binary (TMNB) people with a cervix are much less likely to undergo cervical cancer screening than cisgender women. Transgender women and transfeminine non-binary (TWNB) people assigned male at birth may be at increased risk of HPV. Both TMNB and TWNB people face many barriers to HPV testing including medical mistrust due to stigma and discrimination.Methods and analysis The Self-TI Study (Self-TI) is a pilot study designed to measure acceptability and feasibility of HPV self-testing among transgender and non-binary people in England. TMNB people aged 25-65 years, with at least 1 year of testosterone, and TWNB people, aged 18 years and over, are eligible to participate. Participants self-collect up to four samples: an oral rinse, a first void urine sample, a vaginal swab (if applicable) and an anal swab. TMNB participants are asked to have an additional clinician-collected cervical swab taken following their routine Cervical Screening Programme sample. TWNB people are asked to take a self-collection kit to perform additional self-collection at home and mail the samples back to the clinic. Acceptability is assessed by a self-administered online survey and feasibility is measured as the proportion of samples returned in the clinic and from home.Ethics and dissemination Self-TI received ethical approval from the Research Ethics Committee of Wales 4 and ethical review panel within the Division of Cancer Epidemiology and Genetics at the US National Cancer Institute. Self-TI was coproduced by members of the transgender and non-binary community, who served as authors, collaborators and members of the patient and public involvement (PPI) group. Results of this study will be shared with the community prior to being published in peer-reviewed journals and the PPI group will help to design the results dissemination strategy. The evidence generated from this pilot study could be used to inform a larger, international study of HPV self-testing in the transgender and non-binary community.Trial registration number NCT05883111.

ObjectiveIn order to address the lack of data on the health and healthcare needs of trans and non-binary adults, NHS England includes questions asking about both gender and trans status in its surveys to support quality improvement programmes.We used self-reported data from the GP Patient Survey to answer the research question: what are the demographic characteristics, health conditions and healthcare experiences of trans and non-binary adults in England?Design/settingNationally representative, population-based cross-sectional survey in England with survey data collection from January to March 2021.Participants840 691 survey respondents including 6333 trans and non-binary adults.OutcomesWe calculated weighted descriptive statistics, and using logistic regression explored 15 long-term physical and mental health conditions, and 18 patient experience items, covering overall experience, access, communication and continuity.ResultsTrans and non-binary adults were younger, more likely to be from Asian, black, mixed or other ethnic groups and more likely to live in more deprived parts of the country. Age-specific patterns of long-term conditions were broadly similar among trans and non-binary adults compared with all other survey respondents, with some variation by condition. Overall, inequalities in long-term health conditions were largest for autism: OR (95% CI), 5.8 (5.0 to 6.6), dementia: 3.1 (2.5 to 3.9), learning disabilities: 2.8 (2.4 to 3.2) and mental health: 2.0 (1.9 to 2.2), with variation by age. In healthcare experience, disparities are much greater for interpersonal communication (OR for reporting a positive experience, range 0.4 to 0.7 across items) than access (OR range 0.8 to 1.2). Additionally, trans and non-binary adults report much higher preference for continuity 1.7 (1.6 to 1.8), with no evidence of any differences in being able to see or speak to a preferred general practitioner.ConclusionThis research adds up to date evidence about population demographics, health and healthcare needs to support healthcare improvement for trans and non-binary adults.

Background Transgender and gender diverse (TGD) individuals experience an incongruence between their assigned birth sex and gender identity. They may have a higher prevalence of health conditions associated with cancer risk than cisgender people. Aim To examine the prevalence of several cancer risk factors among TGD individuals compared with cisgender individuals. Design and setting A cross-sectional analysis was conducted using data from the UK’s Clinical Practice Research Datalink to identify TGD individuals between 1988–2020, matched to 20 cisgender men and 20 cisgender women on index date (date of diagnosis with gender incongruence), practice, and index age (age at index date). Assigned birth sex was determined from gender-affirming hormone use and procedures, and sex-specific diagnoses documented in the medical record. Method The prevalence of each cancer risk factor was calculated and the prevalence ratio by gender identity was estimated using log binomial or Poisson regression models adjusted for age and year at study entry, and obesity where appropriate. Results There were 3474 transfeminine (assigned male at birth) individuals, 3591 transmasculine (assigned female at birth) individuals, 131 747 cisgender men, and 131 827 cisgender women. Transmasculine people had the highest prevalence of obesity (27.5%) and ‘ever smoking’ (60.2%). Transfeminine people had the highest prevalence of dyslipidaemia (15.1%), diabetes (5.4%), hepatitis C infection (0.7%), hepatitis B infection (0.4%), and HIV infection (0.8%). These prevalence estimates remained elevated in the TGD populations compared with cisgender persons in the multivariable models. Conclusion Multiple cancer risk factors are more prevalent among TGD individuals compared with cisgender individuals. Future research should examine how minority stress contributes to the increased prevalence of cancer risk factors in this population.

The transgender population face inequalities throughout the cancer pathway. Much of this stems from a lack of access to specialist knowledge of gender-affirming care and how it intersects with cancer. Breast cancer care in particular presents challenges for both patients and clinicians given the interaction with sex hormones , potential to exacerbate dysphoria and differing management in cisgender men vs. cisgender women. Breast cancer risk remains of concern in trans people. The best estimate of breast cancer incidence is trans men and non-binary people assigned female at birth (TMNB) is only 5 times less than in cisgender women. In trans women and non-binary people assigned male at birth (TFNB) the incidence is only 3 times less than in cisgender women. However cancer registries in most countries fail to accurately record gender identity and trans status. In response to this need, we established the UK Cancer and Transition Service (UCATS), a national multidisciplinary team meeting and clinic where any transgender patient with active or historical cancer can access specialist advice and support. This was coproduced with patient and public involvement and input from a specialist cancer charity. We discuss 6 cases of breast cancer in TMNB where cancer and gender-affirming care were mutually impacted by each other. Two of these lead to the establishment of UCATS and a further 4 were managed by the service. Challenges experienced by patients and clinicians included access to satisfactory reconstructive options, access to and management of gender-affirming hormones, and choice of anti-oestrogenic therapy. We recommend introduction similar services internationally and inclusion of gender identity and trans status in cancer registries to improve data collection on cancer risk. Further research is required on the use of gender-affirming hormones in hormone receptor-positive breast cancer in adjuvant and metastatic settings.

It is increasingly recognized that inequalities have an impact on health care outcomes. To drive improvements in care, data are necessary to support better decision making—requiring a combination of improved data capture and willingness of patients to come forward to describe themselves openly. The recent article by Smart et al1Smart AC Liu KX Domogauer JC et al.Gender-affirming surgery and cancer: considerations for radiation oncologists for pelvic radiation in transfeminine patients.Int J Radiat Oncol Biol Phys. 2023; 117: 301-311Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar illustrates the need for specific considerations in pelvic radiation therapy for transfeminine people across a range of malignancies. It gives clear guidance for the planning and delivery of pelvic radiation therapy as well as holistic considerations, including a sensitive approach to the consultation and discussion of sexual function and fertility. The American Society of Clinical Oncology's 2017 position statement2Griggs J Maingi S Blinder V et al.American Society of Clinical Oncology position statement: Strategies for reducing cancer health disparities among sexual and gender minority populations.J Clin Oncol. 2017; 35: 2203-2208Crossref PubMed Scopus (130) Google Scholar highlighted research as a core area of need. Of the 10 action points from the United Kingdom (UK) Joint Collegiate Council for Oncology statement, “Improving Cancer Care for Sexual and Gender Minorities,”3Royal College of Radiologists. Improving cancer care for sexual and gender minorities. Available at: https://www.rcr.ac.uk/posts/improving-cancer-care-sexual-and-gender-minorities. Accessed June 2, 2023.Google Scholar 6 pertained to improvements in data collection and research. Recommendations in both the United States and the UK have been issued for how to monitor gender identity and trans status utilizing a 2-step question,4LGBT Foundation. If we're not counted we don't count - Good practice guide to monitoring sexual orientation and trans status. Available at: https://lgbt.foundation/downloads/ifwerenotcountedwedontcount. Accessed June 2, 2023.Google Scholar,5Becker T Chin M Bates N Measuring Sex, Gender Identity, and Sexual Orientation. National Academies Press, Washington, DC2022Google Scholar where sex registered at birth is separated from gender identity. However, these recommendations have not been incorporated into cancer registries. The North American Association of Central Cancer Registries does contain a sex variable that includes options that allow entry of trans status (having a gender identity that is not the same as the sex that was registered at birth). However, it has been suggested that staff do not routinely utilise these options. This is likely due to lack of training for health care and administrative staff collecting these data in how to ask these questions sensitivty and why the responses are relevant to the patient's healthcare. This results in less inquiry and a reluctance of patients to disclose due to anticipated stigma.6Gomez SL Duffy C Griggs JJ John EM. Surveillance of cancer among sexual and gender minority populations: Where are we and where do we need to go?.Cancer. 2019; 125: 4360-4362Crossref PubMed Scopus (0) Google Scholar This lack of accurate baseline epidemiology on cancer incidence and mortality among transgender individuals has important implications for future research as well as the allocation of clinical resources. Researchers must base hypotheses and grant funding on figures from database studies in which transgender people are treated as one homogenous group rather than disaggregated by sex assigned at birth or gender identity,7Jackson SS Han X Mao Z et al.Cancer stage, treatment, and survival among transgender patients in the United States.J Natl Cancer Inst. 2021; 113: 1221-1227Crossref PubMed Scopus (43) Google Scholar where sex assigned at birth has been inferred,8Alpert AB Komatsoulis GA Meersman SC et al.Identification of transgender people with cancer in electronic health records: Recommendations based on CancerLinQ observations.J Clin Oncol Pract. 2021; 17: e336-e342Google Scholar or worse, on case reports alone. Such sources, while currently valuable as the best available evidence, likely underestimate cancer incidence and mortality as well as the scale of inequalities faced by transgender individuals. This reduces the likely funding success for bespoke intervention studies in areas where there is a higher population density of transgender people. Inclusive monitoring is most useful when paired with more comprehensive clinical data (eg, gender-affirming treatments), patient-reported lifestyle factors, and outcomes measures. Potential benefits include the development of more accurate reference ranges (eg, prostate-specific antigen levels in transfeminine people on gender-affirming hormones, in whom levels may be lower than in cisgender men) and imaging libraries on which to base radiation therapy plans. For transgender individuals undergoing pelvic radiation therapy, such data and further bespoke clinical trials could address many of the questions raised by Smart et al and allow formal consensus guidance in the future. Inclusive monitoring and invitation to bespoke clinical trials requires trust from the transgender community due to historical and ongoing stigma, discrimination, and exploitation. Further, coproduction of this research is essential with involvement of patients, clinicians, and researchers from the transgender community. Increasing trust from patients in the health care system will have the added benefit of increasing disclosure of trans status and the potential to improve outcomes through earlier diagnoses. As Smart et al highlight, we do not know the reasons behind the finding of increased bladder cancer mortality in the transgender population. Late presentation could indeed be a factor, but Jackson et al7Jackson SS Han X Mao Z et al.Cancer stage, treatment, and survival among transgender patients in the United States.J Natl Cancer Inst. 2021; 113: 1221-1227Crossref PubMed Scopus (43) Google Scholar found an increased risk of mortality despite adjustment for stage at presentation. Another cause could be the attribution of urologic symptoms to gender-affirming surgery complications as opposed to malignancy or complexities of surgical or radiation treatment due to gender-affirming care. Without better granularity of data, we cannot know. Dysphoria (psychological discomfort arising from incongruence between gender identity and sex registered at birth) and fear of stigma may also lead to delayed presentation of many sex-related cancers. In prostate cancer, given the indolent nature of many cases, it may result in a lack of presentation altogether. Smart et al highlight the 2014 study by Gooren et al9Gooren L Morgentaler A. Prostate cancer incidence in orchidectomised male-to-female transsexual persons treated with oestrogens.Andrologia. 2014; 46: 1156-1160Crossref PubMed Google Scholar that gives an incidence of 2.0 per 100,000 person-years, though a 2020 study,10de Nie I de Blok CJM van der Sluis TM et al.Prostate cancer incidence under androgen deprivation: Nationwide cohort study in trans women receiving hormone treatment.J Clin Endocrinol Metab. 2020; 105: 3293-3299Crossref PubMed Scopus (8) Google Scholar also from the Netherlands, found an incidence of 16.2 per 100,000 person-years. The latter study had a longer follow-up time to observe cancer development and a larger population due to increased disclosure and presentation for gender-affirming care. Given this context, oncologists are likely to see increasing numbers of transgender patients in their clinic, making the need for evidence-based treatment recommendations all the more urgent. In cases of prostate cancer, as discussed by Smart et al, in which both the options of radiation therapy and surgery may have implications for future gender-affirming surgery, early multidisciplinary team (MDT) discussions are key so as not to limit options available to the patient. One approach being taken in the UK is the UK Cancer and Transition Service,11Transplus. UK Cancer and Transition Service. Available at: https://www.wearetransplus.co.uk/uk-cancer-and-transition-service/. Accessed June 2, 2023.Google Scholar which offers a virtual MDT meeting and clinic appointment with the patient to help integrate cancer and gender-affirming care. All clinicians involved in the patient's care are able to discuss the pros and cons of various treatment approaches, acknowledging uncertainties in the research. This puts the patient at the center of decision making. Having a dedicated time for discussion is important because the various specialists involved may give different levels priority and space to the patients wants and needs. Topics for discussion may include cancer treatment burden, life expectancy, sexual function, and gender-affirming care. MDT networks such as this are important for 2 other reasons. First, they allow building of trust with patients and improve engagement with research and consent to inclusion in registries. Second, they allow a level of on-the-job mutual education of all clinicians involved, developing expertise and the potential for further clinical and research collaboration to the benefit of patients. However, baseline education is required to make clinicians aware of such a service and its utility. Smart et al highlight that radiation planning should account for the patient's history, anatomy, and goals of gender-affirming treatment. They also suggest that radiation oncologists should be “aware of common gender-affirming genitopelvic surgeries.” This requires a level of teaching on gender-affirming care that is lacking from most undergraduate medical and postgraduate oncology training. There have been a number of educational articles addressing this (Table 1), but geographic variation in gender-affirming treatment protocols make a comprehensive understanding out of reach for many physicians. However, acquiring the core language to respectfully approach these conversations is essential, as is knowing where to seek expert opinion when required. As such, these items are included in a chapter titled “Cancer in Lesbian, Gay, Bisexual, Transgender, Queer or Questioning (LGBTQ) Populations” in the forthcoming American Society of Clinical Oncology–European Society of Medical Oncology Global Curriculum (European Society of Medical Oncology, personal communication, March 2023).Table 1Education resourcesTopicResourceTransgender healthColeman E, Radix AE, Bouman WP, et al. Standards of care for the health of transgender and gender diverse people, version 8. Int J Transgender Heal. 2022;23:1-259.Safer JD, Tangpricha V. Care of transgender persons. N Engl J Med. 2019;381:2451-2460.Cancer care for the transgender populationBerner AM, Webster R, Hughes DJ, et al. Education to improve cancer care for LGBTQ+ patients in the UK. Clin Oncol. 2021;33:270-273.Leone AG, Trapani D, Schabath MB, et al. Cancer in transgender and gender-diverse persons: A review. JAMA Oncol. 2023;9:556-563.Quinn GP, Alpert AB, Sutter M, et al. What oncologists should know about treating sexual and gender minority patients with cancer. J Clin Oncol Pract. 2020;16:309-316.Webster R, Drury-Smith H. How can we meet the support needs of LGBT cancer patients in oncology? A systematic review. Radiography. 2020;27:633-644.Resources for transgender patients with cancer and their professionalsLive Through This (https://livethroughthis.co.uk/)National LGBT Cancer Network (https://cancer-network.org/)Queering Cancer (https://queeringcancer.ca/) Open table in a new tab In summary, the oncology community needs to continue to advocate for gender identity and trans status monitoring in cancer registries, in line with appropriate monitoring questions for other minority groups. Proof of the scale of the inequalities is required for appropriate funding of research, and international collaboration is essential to share knowledge and data. The need for tailored research to inform cancer treatments for the transgender population is clear. Experts should collaborate with patient groups and centers specializing in gender-affirming care to establish registries and codesign appropriate research studies. Meanwhile, bespoke clinical services are one way to develop expertise and ensure more equitable person-centered cancer care for the transgender community.

BRCA mutated recurrent platinum sensitive OC patients (pts) who received a maintenance poly-adenosine ribose phosphatase inhibitor (PARPi) show a lower-than-expected response to subsequent chemotherapy in retrospective trial analysis. What are real world outcomes for UK pts, including BRCA wild-type (WT)?. Retrospective data analysis of OC pts who received subsequent chemotherapy following a PARPi (minimum 14 days) between 01/01/18-31/12/21 across 10 UK sites. Responses were evaluated by imaging/CA125 or clinical status, with DCR (defined as CR/PR or SD at first post-chemotherapy assessment, excluding pts with progression). Statistical tests used: Kaplan-Meier (OS and PFS) and Fisher’s Exact Test (DCR and ORR). 311 OC patients: stage III (n = 180, 58%) and IV (n = 106, 34%). 21% were BRCA mutant (MT) (n = 64). PARPis included olaparib (n = 47, 15%), niraparib (n = 220, 71%) and rucaparib (n = 44, 14%), with median duration of use of 189 days (range 14-1351). First post-PARPi chemotherapy was platinum-based (PBC) in 72% (n = 223); 2nd line in 37% (n = 116), 3rd line 47% (n = 147), later line in 15% (n = 48). 234 pts had evaluable responses: ORR to first post-PARPi treatment was 28% for PBC, 27% for non-platinum chemotherapy (NPC) (non-significant, ns); DCR was 44% to PBC, 33% to NPC (ns), median PFS was 5.8 months (m) for PBC, 5.4 m for NPC (ns). Across the 311 pts, median OS was 17.4 m for PBC and 13.6m for NPC (HR 0.56, p = 0.001). Preliminary analysis shows no significant difference in duration of PARPi use, ORR, DCR, according to BRCA status. PFS/OS data will be presented with respect to number of lines and BRCA status. Limitations include retrospective non-trial based follow up.Table: 800PResponse to first post PARPi treatment in 227 pts with known BRCA statusEndpointFirst post PARPi treatmentPlatinum basedNon-platinum basedBRCA MTBRCA WTBRCA MTBRCA WTORR (%)2828OR = 0.99, p = 11728OR = 0.53, p = 1DCR (%)3847OR = 0.70, p = 0.31733OR = 0.41, p = 0.6PFS (m)5.36.1HR = 0.84, p = 0.39.45.4HR = 1.0, p = 1OS (m)18.017.2HR = 0.93, p = 0.715.613.1HR = 0.71, p = 0.4 Open table in a new tab . UK OC patients show similar PFS, OS, ORR and DCR to subsequent treatment following maintenance PARPi irrespective of BRCA status.

Locally advanced oesophageal adenocarcinoma (EAC) remains difficult to treat because of common resistance to neoadjuvant therapy and high recurrence rates. The ecological and evolutionary dynamics responsible for treatment failure are incompletely understood. Here, we performed a comprehensive multi-omic analysis of samples collected from EAC patients in the MEMORI clinical trial, revealing major changes in gene expression profiles and immune microenvironment composition that did not appear to be driven by changes in clonal composition. Multi-region multi-timepoint whole exome (300x depth) and paired transcriptome sequencing was performed on 27 patients pre-, during and after neoadjuvant treatment. EAC showed major transcriptomic changes during treatment with upregulation of immune and stromal pathways and oncogenic pathways such as KRAS, Hedgehog and WNT. However, genetic data revealed that clonal sweeps were rare, suggesting that gene expression changes were not clonally driven. Additional longitudinal image mass cytometry was performed in a subset of 15 patients and T-cell receptor sequencing in 10 patients, revealing remodelling of the T-cell compartment during treatment and other shifts in microenvironment composition. The presence of immune escape mechanisms and a lack of clonal T-cell expansions were linked to poor clinical treatment response. This study identifies profound transcriptional changes during treatment with limited evidence that clonal replacement is the cause, suggesting phenotypic plasticity and immune dynamics as mechanisms for therapy resistance with pharmacological relevance.