The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.
Background: For women with early stage hormone receptor positive breast cancer, adjuvant treatment with tamoxifen reduces their 15-year risk of death from breast cancer by about one third. Aromatase inhibitors (AIs) are even more effective than tamoxifen in post-menopausal women but, used alone, are ineffective in pre-menopausal women due to compensatory ovarian oestrogen production. Several trials have assessed whether, if administered with ovarian suppression, AIs may also be more effective than tamoxifen at preventing breast cancer recurrence in premenopausal women but trial results have been inconsistent. Methods: Individual patient data were available from four randomised controlled trials, including 7,030 pre-menopausal women with estrogen receptor positive (ER+) breast cancer. All women received ovarian suppression or ablation and were randomised to receive either an AI or tamoxifen for 3 years (in ABCSG XII) or 5 years in other trials (SOFT, TEXT and HOBOE). Primary outcomes for the meta-analysis were time to invasive breast cancer recurrence (distant, loco-regional, or new contralateral breast primary) and breast cancer mortality. Log-rank analyses were used to estimate first-event rate ratios (RR) and their confidence intervals (CIs). Results: Overall, the annual rate of recurrence averaged 21% lower (RR 0.79, 95% 0.69-0.90, p=0.0005) for women allocated AI compared to tamoxifen. The main benefit from AI was seen in years 0-4 (RR 0.68, 99% CI 0.58-0.80), during the period when treatments differed, with no further benefit, or loss of benefit, in years 5-9 (RR 0.98, 99% 0.73-1.32), and as yet limited follow up data available beyond year 10. The 5-year absolute risk of breast cancer recurrence was 3.2% lower in the AI group than the tamoxifen group (6.9% vs 10.1%, p=0.0005). Although distant recurrence was reduced with AI (RR 0.83, 95% CI 0.71-0.97, p=0.02), there was no difference in breast cancer mortality although longer follow up is needed to assess effects on mortality reliably. The proportional reduction in recurrence during the period when treatments differed did not vary by age, BMI, or by tumour size, tumour grade, histological subtype, or presence and absence of chemotherapy. In contrast to the findings of the meta-analysis of AI vs tamoxifen in postmenopausal women, AI appeared ineffective in N4+ disease (RR=0.49 in N0, RR=0.56 in N1-3, RR=1.03 in N4+; p for trend =0.0009). The only other apparent heterogeneity was between the four trial results (p=0.03), and between HER2-negative and positive disease (p=0.05), which may be chance findings given the borderline statistical significance. There were more bone fractures in women receiving AI (5.0% AI vs 3.8% Tam, p=0.02). Among these younger women, few non-breast cancer deaths occurred: 0.9% AI vs 0.7% Tam (RR 1.30, 95% CI 0.75-2.25), and the incidence of endometrial cancer was low (0.2% AI vs 0.3% tamoxifen, p=0.14). Conclusion: Using an AI rather than tamoxifen, in premenopausal women receiving ovarian suppression, reduces the risk of breast cancer recurrence by about 20%. If the surprising lack of benefit in N4+ disease is a chance finding, then the absolute benefits will be larger for women at a higher absolute risk of recurrence. Citation Format: Rosie Bradley, Jeremy Braybrooke, Richard Gray, Robert K Hills, Zulian Lui, Hongchao Pan, Richard Peto, Jonas Bergh, Sandra M Swain, Prudence Francis, Michael Gnant, Francesco Perrone, Meredith M Regan. Aromatase inhibitors versus tamoxifen in pre-menopausal women with estrogen receptor positive early stage breast cancer treated with ovarian suppression: A patient level meta-analysis of 7,030 women in four randomised trials [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-04.
374 Background: Survival after orchiectomy in stage I seminoma is almost 100%. CT surveillance is an international standard of care, and avoids adjuvant therapy. In this young population, who are unlikely to die from testicular cancer, minimizing irradiation is vital. The Trial of Imaging and Surveillance in Seminoma Testis (TRISST, NCT00589537), assessed whether CTs can safely be reduced, or replaced with MRI, without an unacceptable increase in advanced relapses. Methods: TRISST is a phase III, multicenter, non-inferiority, factorial trial. Eligible men had undergone orchiectomy for stage I seminoma with no adjuvant therapy planned. Randomization was to: 7 CTs (6, 12, 18, 24, 36, 48, 60 months (m) after randomization); 7 MRIs (same schedule); 3 CTs (6, 18, 36m); or 3 MRIs (same schedule). Follow-up was for 6 years. The primary outcome is 6-year incidence of RMH stage ≥IIC relapse, aiming to exclude an increase ≥5.7% (from 5.7% to 11.4%) with MRI (vs CT) or 3 scans (vs 7); target n=660, all contributing to both comparisons. Secondary outcomes include relapse ≥3cm, disease-free and overall survival (DFS, OS). Results: 669 men enrolled from 35 UK centers (2008-2014); mean tumor size 2.9cm, 358 (54%) were low risk (≤4cm, no rete testis invasion). Median follow-up was 72m. 82 (12%) patients relapsed. Incidence of stage ≥IIC relapse was low in all groups (n=10). More events occurred with 3 scans vs 7, though non-inferior based on design criteria: 9 (2.8%) vs 1 (0.3%), 2.5% increase, 90% CI 1.0% to 4.1% (intent-to-treat, ITT). 4/9 in 3-scan arms could potentially have been detected earlier with the 7-scan schedule. Fewer events occurred with MRI vs CT: 2 (0.6%) vs 8 (2.5%), 1.9% decrease, 90% CI -3.5% to -0.3% (ITT). Per protocol results were similar. Incidence of relapse ≥3cm was 3.7%; non-inferiority was shown for both comparisons. In all groups, most relapses were detected at scheduled imaging; very few occurred beyond 3 years (5 in 558 at risk, <1%). Relapse treatment outcomes were good (81% complete response) with no tumor-related deaths. 5-year DFS and OS were 87% and 99%, similar across groups. Conclusions:Surveillance is a safe management approach in stage I seminoma – advanced relapse is rare, salvage treatment successful, and long-term outcomes excellent, regardless of imaging frequency or modality. Relapse beyond 3 years is rare and imaging may be unnecessary. MRI is non-inferior to CT, avoids irradiation and should be recommended. Clinical trial information: NCT00589537.
Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting.
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