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.
<div>Abstract<p>There is limited knowledge on the benefit of the α-subunit–specific PI3K inhibitor alpelisib in later lines of therapy for advanced estrogen receptor–positive (ER<sup>+</sup>) HER2<sup>−</sup> and triple-negative breast cancer (TNBC). We conducted a phase II multicohort study of alpelisib monotherapy in patients with advanced PI3K pathway mutant ER<sup>+</sup>HER2<sup>−</sup> and TNBC. In the intention-to-treat ER<sup>+</sup> cohort, the overall response rate was 30% and the clinical benefit rate was 36%. A decline in PI3K pathway mutant circulating tumor DNA (ctDNA) levels from baseline to week 8 while on therapy was significantly associated with a partial response, clinical benefit, and improved progression-free-survival [HR 0.24; 95% confidence interval (CI), 0.083–0.67, <i>P</i> = 0.0065]. Detection of <i>ESR1</i> mutations at baseline in plasma was also associated with clinical benefit and improved progression-free survival (HR 0.22; 95% CI, 0.078–0.60, <i>P</i> = 0.003).</p>Significance:<p>Alpelisib monotherapy displayed efficacy in heavily pretreated ER<sup>+</sup> breast cancer with <i>PIK3CA</i> mutations. <i>PIK3CA</i> mutation dynamics in plasma during treatment and <i>ESR1</i> mutations detected in plasma at baseline were candidate biomarkers predictive of benefit from alpelisib, highlighting the utility of ctDNA assays in this setting.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-12-9-ITI" target="_blank">This article is highlighted in the In This Issue feature, p. 2007</a></i></p></div>
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.
<div>Abstract<p>There is limited knowledge on the benefit of the α-subunit–specific PI3K inhibitor alpelisib in later lines of therapy for advanced estrogen receptor–positive (ER<sup>+</sup>) HER2<sup>−</sup> and triple-negative breast cancer (TNBC). We conducted a phase II multicohort study of alpelisib monotherapy in patients with advanced PI3K pathway mutant ER<sup>+</sup>HER2<sup>−</sup> and TNBC. In the intention-to-treat ER<sup>+</sup> cohort, the overall response rate was 30% and the clinical benefit rate was 36%. A decline in PI3K pathway mutant circulating tumor DNA (ctDNA) levels from baseline to week 8 while on therapy was significantly associated with a partial response, clinical benefit, and improved progression-free-survival [HR 0.24; 95% confidence interval (CI), 0.083–0.67, <i>P</i> = 0.0065]. Detection of <i>ESR1</i> mutations at baseline in plasma was also associated with clinical benefit and improved progression-free survival (HR 0.22; 95% CI, 0.078–0.60, <i>P</i> = 0.003).</p>Significance:<p>Alpelisib monotherapy displayed efficacy in heavily pretreated ER<sup>+</sup> breast cancer with <i>PIK3CA</i> mutations. <i>PIK3CA</i> mutation dynamics in plasma during treatment and <i>ESR1</i> mutations detected in plasma at baseline were candidate biomarkers predictive of benefit from alpelisib, highlighting the utility of ctDNA assays in this setting.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-12-9-ITI" target="_blank">This article is highlighted in the In This Issue feature, p. 2007</a></i></p></div>
Abstract Background: Addition of taxanes to adjuvant chemotherapy provides survival benefit in patients with early breast cancer (EBC). Intensifying adjuvant regimens with taxanes leads to increased toxicity, including higher rates of sensory peripheral neuropathy (sPN). Prevalence of chemotherapy induced peripheral neuropathy (CIPN) in trials varies with reported rates of 15 - 30%. Up to 15% of patients report persistent CIPN 1-3 years post treatment with associated adverse impact on quality of life (QOL). There is limited data reporting rates of CIPN and QOL beyond 3 years. We assessed rates of persistent sPN in real world patients with EBC treated with adjuvant taxanes and its effect on QOL. Methods: Patients who received adjuvant taxane for EBC at a metropolitan health service in the preceding 10 years were identified from hospital records and invited to participate. Data was collected at a single time point using the EORTC Quality of Life (QLQ30) and Chemotherapy-Induced Peripheral Neuropathy (CIPN20) questionnaires. Demographic, co-morbid and treatment details were collected from medical records. Raw scores were linearly transformed to a 0 to 100 scale with higher scores indicating higher functioning, QOL and levels of symptomatology. Prevalence was determined using a binary model of no or any sPN and cases grouped into no/mild or moderate/severe for further analysis. Groupwise comparisons were performed with parametric and non-parametric tests. Analysis of covariance was used to fit models incorporating comorbid factors such as diabetes with time point of assessment as the covariate. Results: 176 of 250 questionnaires were returned, a response rate of 71%. Median age was 59 (range 30-88 years) with 52% of respondents receiving paclitaxel vs 47% docetaxel containing regimens. Median time from completion of taxane was 30 months (range 6-120 months). 11 patients (6%) had known diabetes and 50 (26%) had at least one other known risk factor for neuropathy. The prevalence of CIPN across all time points was 74.4%, much higher than seen in historical trials. Table 1: Incidence of sensory neuropathy (all grades) by time from chemotherapyTime bracket (months)N= (176)PN (%)No PN (%)6-246352 (82.5)11 (17.5)25-486347 (74.6)16 (25.4)49-1205032 (64%)18 (36%) QOL scores were lower in patients with moderate/severe sPN, with a median global QOL scaled score of 50 vs 75 in patient with no/mild sPN (p = 0.0062). Increasing sPN score was associated with lower QOL score controlling for time from chemotherapy (standardised beta co-efficient -0.28). In an analysis of covariance, diabetes was the only significant comorbid factor associated with higher sPN scores. In the final model incorporating diabetes, miscellaneous other sPN risk factors and time from chemotherapy, diabetes was associated with increased sPN scores with a small effect size (p = 0.03). Paclitaxel was associated with higher sPN scores than docetaxel (p 0.0001) with significant interaction of paclitaxel with diabetes independent of other sPN risk factors and time from chemotherapy (p = 0.02). Paclitaxel was associated with higher sPN scores in diabetic patients (adjusted mean score in diabetic patients 46.7 v 20.9 in non-diabetic receiving paclitaxel, p = 0.001). Conclusion: CIPN is significantly more prevalent in this real world cohort than reported in historic data, with persistent sPN having a negative correlation with QOL out to 10 years. Higher rates of paclitaxel-associated sPN in diabetic patients could inform decision making on adjuvant chemotherapy. Citation Format: Elizabeth F Blackley, Megan G Kesper, Peter Savas, Bianca Devitt. Long-term incidence of taxane induced peripheral neuropathy in early breast cancer patients, a real world, single centre experience exploring effects on health related quality of life [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-17-06.
Abstract There is limited knowledge on the benefit of the α-subunit–specific PI3K inhibitor alpelisib in later lines of therapy for advanced estrogen receptor–positive (ER+) HER2− and triple-negative breast cancer (TNBC). We conducted a phase II multicohort study of alpelisib monotherapy in patients with advanced PI3K pathway mutant ER+HER2− and TNBC. In the intention-to-treat ER+ cohort, the overall response rate was 30% and the clinical benefit rate was 36%. A decline in PI3K pathway mutant circulating tumor DNA (ctDNA) levels from baseline to week 8 while on therapy was significantly associated with a partial response, clinical benefit, and improved progression-free-survival [HR 0.24; 95% confidence interval (CI), 0.083–0.67, P = 0.0065]. Detection of ESR1 mutations at baseline in plasma was also associated with clinical benefit and improved progression-free survival (HR 0.22; 95% CI, 0.078–0.60, P = 0.003). Significance: Alpelisib monotherapy displayed efficacy in heavily pretreated ER+ breast cancer with PIK3CA mutations. PIK3CA mutation dynamics in plasma during treatment and ESR1 mutations detected in plasma at baseline were candidate biomarkers predictive of benefit from alpelisib, highlighting the utility of ctDNA assays in this setting. This article is highlighted in the In This Issue feature, p. 2007
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 .
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