Abstract Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring.
Prognosis remains poor for patients with relapsed or refractory Ewing sarcoma, with limited treatment options after first‐line therapy. Oral etoposide has efficacy in the paediatric setting; however, data are limited in adults. A retrospective analysis was conducted on 33 patients with relapsed or refractory Ewing sarcoma who completed at least one cycle of oral etoposide at the Peter MacCallum Cancer Centre from 2005 to 2020. The median age at diagnosis and first relapse was 21 and 23 years, respectively. All patients had prior exposure to intravenous etoposide. Nine patients (27%) had stable disease for at least 6 months, and six patients (18%) had a partial response. The clinical benefit rate was 45%. The median PFS was 3.6 months (95% CI: 1.7–5.5), and OS was 8.5 months (95% CI: 4.1–13.0). Despite prior exposure, oral etoposide demonstrated antitumour activity and durable responses in the relapsed or refractory setting for adult patients with Ewing sarcoma.
The Victorian Precision Oncology Summit, convened in 2023, was a joint initiative between the Victorian Comprehensive Cancer Centre Alliance (VCCC Alliance) and the Monash Partners Comprehensive Cancer Consortium (MPCCC) and was proposed to guide a coordinated state-wide conversation about how the oncology sector can overcome some of the current obstacles in achieving equity of access to clinical cancer genomics for Victorian patients. Themes that emerged from discussion groups at the Summit include standardisation, centralisation, funding, education and communication and insights across those themes are outlined in this manuscript. The event served as a large consultation piece for the development of a broader precision oncology roadmap, which explores equitable access to molecular testing for Victorian patients, currently in development by the VCCC Alliance and MPCCC in collaboration with other key Victorian and national stakeholders. While this symposium was a Victorian initiative, it is felt that the insights garnered from this consultation piece will be of interest to consumer groups, clinicians, researchers, educators, policy makers and other key stakeholders in other states of Australia as well as in other countries implementing comprehensive genomic profiling within complex health systems.
Abstract Background RG6292 is the first anti-human CD25 antibody developed to specifically deplete human Tregs while preserving IL-2R STAT5 signaling and Teff activity. Methods Patients with advanced/metastatic solid tumors and without standard treatment options were enrolled in dose escalation studies and received RG6292 i.v. Q3W as monotherapy (S1: NCT04158583) or in combination with atezolizumab 1200 mg Q3W (S2: NCT04642365) until disease progression or unacceptable toxicities to determine the maximum tolerated dose (MTD) and/or optimal biological dose, safety and preliminary clinical activity. DLT window was 4 weeks and dose increments were determined by a Bayesian-based continuous reassessment method (CRM) with overdose control. Adverse events (AEs) were graded by NCI CTCAE v5.0. Tumors were assessed by RECIST 1.1 every 8 weeks in the first year and then every 12 weeks. Results As of 27th May, 2022, 76 patients have been treated with RG6292 monotherapy (dose ranging from 0.3 - 165 mg). Six DLTs were reported, including rash, papular rash, rash macular-papular, AST elevation and ALT elevation. MTD is 165 mg. Seventy-five patients (99%) experienced at least one AE. The most common AEs were pruritus (32%), rash (29%) and fatigue (29%). Thirty-five patients (46%) experienced grade ≥ 3 AEs and 2 patients discontinued from study treatment due to AEs. Fourteen patients (18%) experienced grade ≥ 3 TRAEs. No AEs led to a fatal outcome. Median treatment duration was 43 days. Twenty-three patients have SD as best overall response. Forty-eight patients have been treated with RG6292 (dose ranging from 0.3 - 160 mg) in combination with atezolizumab. Two DLTs were reported, including immune system disorder and maculopapular rash. MTD has not been reached. Forty-seven patients (98%) experienced at least one AE. The most common AEs reported were pruritus (44%), rash (33%) and fatigue (33%). Twenty patients (42%) experienced grade ≥3 AEs and 2 patients discontinued from study treatment due to AEs. Five patients (10%) experienced grade ≥3 TRAEs. No AEs led to a fatal outcome. Median treatment duration was 54 days. Pruritus and rash were expected AEs and easily managed withtopical steroids or short course, low dose systemic steroids. Two patients have PR and 19 patients have SD as best overall response. Conclusion RG6292 is well tolerated and has a manageable safety profile as a single agent and in combination with atezolizumab. The preliminary safety and clinical activity from dose-escalation warrant further investigation of RG6292. Citation Format: Valentina Gambardella, Michael Ong, Maria Esperanza Rodriguez Ruiz, Jean-Pascal Machiels, Miguel Fernandez de Sanmamed, Josep Maria Tabernero, Anna Spreafico, Daniel J Renouf, Stephen J Luen, Rachel Galot, Bernard Doger de Speville Uribe, Emiliano Calvo Aller, Aung Naing, Samira Curdt, Eva Rossmann, Tamara Tanos, Kevin Smart, Maria Amann, Yuying Xie, Gabriel Schnetzler, Christophe Boetsch, Vaios Karanikas, Theresa Kolben, Linxinyu Xu, Kristoffer S Rohrberg. Safety and anti-tumor activity of a novel Treg depleter RG6292, as a single agent and in combination with atezolizumab in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT110.
The role of adaptive immunity in long-term outcomes in early breast cancer is increasingly recognised. Standard (neo)adjuvant chemotherapy can have adverse effects on immune cells. We conducted a retrospective longitudinal study of full blood counts (FBC) of 200 patients receiving (neo)adjuvant chemotherapy for early breast cancer at a single institution. FBC results at four time points from pre-treatment to 12 months post-chemotherapy were analysed. Flow cytometry was performed for patients with matched pre- and post-chemotherapy peripheral blood mononuclear cell samples. A significant decrease in absolute lymphocyte count at 12 months post-chemotherapy was observed (p < 0.01), most pronounced in pre-menopausal patients (n = 73; p < 0.01), patients receiving dose-dense chemotherapy regimens (n = 60; p < 0.01) and patients receiving adjuvant radiotherapy (n = 147, p < 0.01). In pre-menopausal patients, significant changes in CD4+ T cells subsets post-chemotherapy were observed. Further investigation, including long-term clinical outcomes, is needed to meaningfully improve long-term anti-tumour immunity.
571 Background: For primary TNBCs treated with NAC, higher pre-treatment TILs correlate with increased pathological complete response (pCR) rates, better recurrence-free survival (RFS) and overall survival (OS). We evaluated the prognostic value of RD TILs to pathological stage and Residual Cancer Burden (RCB) in predicting survival post NAC. Methods: We combined individual patient data from 4 TNBC patient series treated with NAC who did not achieve pCR. TILs were evaluated on the RD using our previously published method on H&E stained slides. TILs were investigated for associations with yp stage, RCB, RFS and OS using Cox models with stromal TILs as a continuous variable, stratified by series. The likelihood ratio (LR) test was used to evaluate added prognostic value of TILs to standard yp stage and RCB class. Results: In total 376 RD samples were evaluable for TILs. After 6 years median follow-up we observed 193 RFS events and 165 deaths. The median age was 50 years (range 24-83). 62% received combination anthracycline/taxane chemotherapy, and 27% anthracycline alone. For RD stage, 32% were yp node positive; RCB class I/II/III was 11%/50%/39% respectively. The median RD TIL level was 20% (IQR 10-40). TIL levels were significantly lower with increasing yp stage (P < 0.01), but did not differ significantly by RCB class (P = 0.84). Higher RD TILs were significantly associated with improved RFS (HR per 10% increment 0.86; 95%CI 0.79-0.92; P < 0.01) and OS (HR 0.87; 95%CI 0.80-0.94; P < 0.01), but were only significant for RFS in multivariate analysis after adjusting for yp stage (P = 0.03). RCB class was significant for RFS and OS (both P < 0.01). RD TILs added significant prognostic value to RCB class for both RFS and OS (both LR P < 0.01). The positive prognostic effect of RD TILs was of greater magnitude in the lower RCB classes I/II vs. III for both RFS and OS (both interaction P < 0.01). Conclusions: TIL levels in TNBC RD are significantly associated with improved RFS and OS and add further prognostic information to RCB class. The positive prognostic influence of TILs is significantly greater in patients with less RD burden. This data may help refine NAC clinical trial endpoints.
Abstract Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls .
There is now accumulating evidence that the host immune system plays an important role in influencing response to treatment and prognosis in breast cancer. Immunotherapy with immune checkpoint inhibitors is a promising and rapidly growing field of interest in many solid tumours, including breast cancer. Trials to date have largely focused on metastatic triple-negative disease, a genomically unstable subtype of breast cancer that is believed to be the most immunogenic and following the development of treatment resistance, has limited treatment options and a particularly poor prognosis. Both checkpoint inhibitor monotherapy and combinations with chemotherapy are being investigated. In this review, we discuss the current evidence for PD-1/PD-L1 blockade in metastatic triple-negative breast cancer (TNBC), HER2+ breast cancer and ER+ disease, as well as the emerging evidence for use in the early-stage (neoadjuvant) setting. We also propose potential ways of improving responses to checkpoint blockade in breast cancer.
Abstract Background Pamiparib is a potent, selective, poly (ADP‐ribose) polymerase 1/2 inhibitor that demonstrates synthetic lethality in cells with breast cancer susceptibility gene mutations or other homologous recombination deficiency. This two‐stage phase 1b study (NCT03150810) assessed pamiparib in combination with temozolomide (TMZ) in adult patients with histologically confirmed locally advanced and metastatic solid tumors. Methods Oral pamiparib 60 mg was administered twice daily. During the dose‐escalation stage, increasing doses of TMZ (40–120 mg once daily pulsed or 20–40 mg once daily continuous) were administered to determine the recommended dose to be administered in the dose‐expansion stage. The primary objectives were to determine safety and tolerability, maximum tolerated/administered dose, recommended phase 2 dose and schedule, and antitumor activity of pamiparib in combination with TMZ. Pharmacokinetics of pamiparib and TMZ and biomarkers were also assessed. Results Across stages, 139 patients were treated (dose escalation, n = 66; dose expansion, n = 73). The maximum tolerated dose of TMZ, which was administered during dose expansion, was 7‐day pulsed 60 mg once daily. The most common treatment‐emergent adverse events (TEAEs) were anemia (dose escalation, 56.1%; dose expansion, 63.0%), nausea (dose escalation, 54.5%; dose expansion, 49.3%), and fatigue (dose escalation, 48.5%; dose expansion, 47.9%). In the dose‐escalation stage, four patients experienced dose‐limiting toxicities (three neutropenia and one neutrophil count decreased). No TEAEs considered to be related to study drug treatment resulted in death. Antitumor activity was modest, indicated by confirmed overall response rate (dose escalation, 13.8%; dose expansion, 11.6%), median progression‐free survival (3.7 and 2.8 months), and median overall survival (10.5 and 9.2 months). Administration of combination therapy did not notably impact pamiparib or TMZ pharmacokinetics. Conclusions Pamiparib in combination with TMZ had a manageable safety profile. Further investigation of the efficacy of this combination in tumor types with specific DNA damage repair deficiencies is warranted.
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