Breast Cancer Research
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Item Capturing longer term surgical outcome measures as part of routine care of breast cancer patients.(CHURCHILL LIVINGSTONE, 2024-08-01) Leusink, AE; Godden, AR; Yildirim, N; Randawa, A; Law, R; Rusby, JE; Leusink, AstridINTRODUCTION: The transition away from routine clinical follow up after breast cancer towards imaging surveillance and patient-initiated contact limits opportunities for patients and doctors to communicate about the long-term effects of treatment. The ABS oncoplastic guidelines (2021) recommend that post-operative 2D images and patient-reported outcomes (PROMs) are routinely collected but give no guidance as to how best to implement this. METHODS: From December 2019 until March 2024, women due for their year 3 or 5 surveillance mammogram at The Royal Marsden Sutton site were invited to complete a BREAST-Q questionnaire and attend medical photography. Panel assessment of photographs was undertaken. Results were presented to the oncoplastic MDT, including summary PROMs and illustrative case presentations. Free-text comments were shared with the relevant teams. Associations between demographic or clinic-pathological factors and uptake were investigated. RESULTS: Of the 1211 women invited, 246 patients (20.3 %) completed BREAST-Q questionnaires, 182 (15.0 %) attended for medical photography and 114 (9.4 %) completed both. Uptake was not associated with age, ethnicity or surgical factors but patients with higher BMI were less likely to respond to the questionnaire. Patients who had undergone complex oncoplastic procedures were more likely to respond than those who had simple procedures. Patient-reported outcome results were in line with the published literature. CONCLUSION: Reviewing images with their paired PROMs and discussing free-text feedback was instructive for the team. Work is needed to identify barriers to patient participation and improve uptake to be representative of the overall patient population. Quantifying appearance in photographs would help summarise aesthetic outcome data.Item Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma.(American Association for Cancer Research (AACR), 2024-08-15) Saner, FAM; Takahashi, K; Budden, T; Pandey, A; Ariyaratne, D; Zwimpfer, TA; Meagher, NS; Fereday, S; Twomey, L; Pishas, KI; Hoang, T; Bolithon, A; Traficante, N; Australian Ovarian Cancer Study Group; Alsop, K; Christie, EL; Kang, E-Y; Nelson, GS; Ghatage, P; Lee, C-H; Riggan, MJ; Alsop, J; Beckmann, MW; Boros, J; Brand, AH; Brooks-Wilson, A; Carney, ME; Coulson, P; Courtney-Brooks, M; Cushing-Haugen, KL; Cybulski, C; El-Bahrawy, MA; Elishaev, E; Erber, R; Gayther, SA; Gentry-Maharaj, A; Gilks, CB; Harnett, PR; Harris, HR; Hartmann, A; Hein, A; Hendley, J; Hernandez, BY; Jakubowska, A; Jimenez-Linan, M; Jones, ME; Kaufmann, SH; Kennedy, CJ; Kluz, T; Koziak, JM; Kristjansdottir, B; Le, ND; Lener, M; Lester, J; Lubiński, J; Mateoiu, C; Orsulic, S; Ruebner, M; Schoemaker, MJ; Shah, M; Sharma, R; Sherman, ME; Shvetsov, YB; Soong, TR; Steed, H; Sukumvanich, P; Talhouk, A; Taylor, SE; Vierkant, RA; Wang, C; Widschwendter, M; Wilkens, LR; Winham, SJ; Anglesio, MS; Berchuck, A; Brenton, JD; Campbell, I; Cook, LS; Doherty, JA; Fasching, PA; Fortner, RT; Goodman, MT; Gronwald, J; Huntsman, DG; Karlan, BY; Kelemen, LE; Menon, U; Modugno, F; Pharoah, PDP; Schildkraut, JM; Sundfeldt, K; Swerdlow, AJ; Goode, EL; DeFazio, A; Köbel, M; Ramus, SJ; Bowtell, DDL; Garsed, DW; Jones, Michael; Schoemaker, MinoukPURPOSE: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). EXPERIMENTAL DESIGN: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss. RESULTS: RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. CONCLUSIONS: Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.Item A single-centre study evaluating a geriatric screening tool in oncology phase I trial patients.(WILEY, 2024-06-01) Van Zyl, M; Barell, A; Cooley, B; Hanwell, J; Parlak, J; Banerji, U; De Bono, J; Sharp, A; Lopez, J; Battisti, NML; Minchom, A; Banerji, Udai; De Bono, Johann; Sharp, Adam; Battisti, Nicolo; Minchom, AnnaBACKGROUND: Though cancer is more prevalent in the older population, this patient group are underrepresented in phase I oncology trials. AIMS: We evaluated the use of a geriatric screening tool (SAOP3) in patients of 70 years of age or older who attended a Phase I Clinical Trials Unit, with the aim of assessing the feasibility of the tool and identifying potential unmet needs in this patient group. METHODS: Twenty-two patients over the age of 70 completed the SAOP3 questionnaire. Geriatric impairments and needs were analysed with descriptive statistics. Qualitative responses were grouped in themes using structured thematic analysis. RESULTS: All of patients triggered at least 1 geriatric domain, most commonly mobility. Six core themes were identified as being important to the patient including family, friends and positivity. On cognition assessment over 20% of patients triggered as requiring further cognitive assessment. The group had a relatively high screen fail risk. CONCLUSION: In conclusion, routine geriatric screening withSAOP3 was feasible and identified areas of patient need. Results highlight the prevalence of psychological distress and cognitive impairment. Geriatric screening offers an opportunity for prehabilitation prior to trial and support during trial participation to optimise safety and improve trial access.Item Anti-EGFR Antibody-Drug Conjugate Carrying an Inhibitor Targeting CDK Restricts Triple-Negative Breast Cancer Growth.(American Association for Cancer Research (AACR), 2024-08-01) Cheung, A; Chenoweth, AM; Johansson, A; Laddach, R; Guppy, N; Trendell, J; Esapa, B; Mavousian, A; Navarro-Llinas, B; Haider, S; Romero-Clavijo, P; Hoffmann, RM; Andriollo, P; Rahman, KM; Jackson, P; Tsoka, S; Irshad, S; Roxanis, I; Grigoriadis, A; Thurston, DE; Lord, CJ; Tutt, ANJ; Karagiannis, SN; Lord, Christopher; Tutt, AndrewPURPOSE: Anti-EGFR antibodies show limited response in breast cancer, partly due to activation of compensatory pathways. Furthermore, despite the clinical success of cyclin-dependent kinase (CDK) 4/6 inhibitors in hormone receptor-positive tumors, aggressive triple-negative breast cancers (TNBC) are largely resistant due to CDK2/cyclin E expression, whereas free CDK2 inhibitors display normal tissue toxicity, limiting their therapeutic application. A cetuximab-based antibody drug conjugate (ADC) carrying a CDK inhibitor selected based on oncogene dysregulation, alongside patient subgroup stratification, may provide EGFR-targeted delivery. EXPERIMENTAL DESIGN: Expressions of G1/S-phase cell cycle regulators were evaluated alongside EGFR in breast cancer. We conjugated cetuximab with CDK inhibitor SNS-032, for specific delivery to EGFR-expressing cells. We assessed ADC internalization and its antitumor functions in vitro and in orthotopically grown basal-like/TNBC xenografts. RESULTS: Transcriptomic (6,173 primary, 27 baseline, and matched post-chemotherapy residual tumors), single-cell RNA sequencing (150,290 cells, 27 treatment-naïve tumors), and spatial transcriptomic (43 tumor sections, 22 TNBCs) analyses confirmed expression of CDK2 and its cyclin partners in basal-like/TNBCs, associated with EGFR. Spatiotemporal live-cell imaging and super-resolution confocal microscopy demonstrated ADC colocalization with late lysosomal clusters. The ADC inhibited cell cycle progression, induced cytotoxicity against high EGFR-expressing tumor cells, and bystander killing of neighboring EGFR-low tumor cells, but minimal effects on immune cells. Despite carrying a small molar fraction (1.65%) of the SNS-032 inhibitor, the ADC restricted EGFR-expressing spheroid and cell line/patient-derived xenograft tumor growth. CONCLUSIONS: Exploiting EGFR overexpression, and dysregulated cell cycle in aggressive and treatment-refractory tumors, a cetuximab-CDK inhibitor ADC may provide selective and efficacious delivery of cell cycle-targeted agents to basal-like/TNBCs, including chemotherapy-resistant residual disease.Item A functional survey of the regulatory landscape of estrogen-receptor-positive breast cancer evolution.(American Association for Cancer Research (AACR), 2024-05-16) Barozzi, I; Slaven, N; Canale, E; Lopes, R; Amorim Monteiro Barbosa, I; Bleu, M; Ivanoiu, D; Pacini, C; Mensa, E; Chambers, A; Bravaccini, S; Ravaioli, S; Gyorffy, B; Dieci, MV; Pruneri, G; Galli, GG; Magnani, L; Magnani, LucaOnly a handful of somatic alterations have been linked to endocrine therapy resistance in hormone-dependent breast cancer (HDBC), potentially explaining ~40% of relapses. If other mechanisms underlie the evolution of HDBC under adjuvant therapy is currently unknown. In this work, we employ functional genomics to dissect the contribution of cis-regulatory elements (CREs) to cancer evolution by focusing on 12 megabases of non-coding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Parallel epigenetic perturbation (CRISPRi) in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies a limited set of non-coding changes potentially involved in therapy resistance. Overall, our data uncover how endocrine therapies triggers the emergence of transient features which could ultimately be exploited to hinder the adaptive process.