Ductal carcinoma in situ: to treat or not to treat, that is the question

Abstract: Ductal carcinoma in situ (DCIS) now represents 20–25% of all ‘breast cancers’ consequent upon detection by population-based breast cancer screening programmes. Currently, all DCIS lesions are treated, and treatment comprises either mastectomy or breast-conserving surgery supplemented with radiotherapy. However, most DCIS lesions remain indolent. Difficulty in discerning harmless lesions from potentially invasive ones can lead to overtreatment of this condition in many patients. To counter overtreatment and to transform clinical practice, a global, comprehensive and multidisciplinary collaboration is required. Here we review the incidence of DCIS, the perception of risk for developing invasive breast cancer, the current treatment options and the known molecular aspects of progression. Further research is needed to gain new insights for improved diagnosis and management of DCIS, and this is integrated in the PRECISION (PREvent ductal Carcinoma In Situ Invasive Overtreatment Now) initiative. This international effort will seek to determine which DCISs require treatment and prevent the consequences of overtreatment on the lives of many women affected by DCIS

A pooled analysis evaluating prognostic significance of Residual Cancer Burden in invasive lobular breast cancer.

Residual Cancer Burden (RCB) after neoadjuvant chemotherapy (NAC) is validated to predict event-free survival (EFS) in breast cancer but has not been studied for invasive lobular carcinoma (ILC). We studied patient-level data from a pooled cohort across 12 institutions. Associations between RCB index, class, and EFS were assessed in ILC and non-ILC with mixed effect Cox models and multivariable analyses. Recursive partitioning was used in an exploratory model to stratify prognosis by RCB components. Of 5106 patients, the diagnosis was ILC in 216 and non-ILC in 4890. Increased RCB index was associated with worse EFS in both ILC and non-ILC (p = 0.002 and p < 0.001, respectively) and remained prognostic when stratified by receptor subtype and adjusted for age, grade, T category, and nodal status. Recursive partitioning demonstrated residual invasive cancer cellularity as most prognostic in ILC. These results underscore the utility of RCB for evaluating NAC response in those with ILC

Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

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

Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Funder: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)Funder: National Center for Research Resources under award number 1 C06 RR12463-01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University.Funder: Susan G Komen Foundation (CCR CCR18547966) and a Young Investigator Grant from the Breast Cancer Alliance.Funder: The Canadian Cancer SocietyFunder: Breast Cancer Research Foundation (BCRF), Grant No. 17-194Abstract: 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

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Funder: Breast Cancer Research Foundation (BCRF); doi: https://doi.org/10.13039/100001006Abstract: 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

Prognostic value of histopathological DCIS features in a large-scale international interrater reliability study

PURPOSE For optimal management of ductal carcinoma in situ (DCIS), reproducible histopathological assessment is essential to distinguish low-risk from high-risk DCIS. Therefore, we analyzed interrater reliability of histopathological DCIS features and assessed their associations with subsequent ipsilateral invasive breast cancer (iIBC) risk. METHODS Using a case-cohort design, reliability was assessed in a population-based, nationwide cohort of 2767 women with screen-detected DCIS diagnosed between 1993 and 2004, treated by breast-conserving surgery with/without radiotherapy (BCS ± RT) using Krippendorff's alpha (KA) and Gwet's AC2 (GAC2). Thirty-eight raters scored histopathological DCIS features including grade (2-tiered and 3-tiered), growth pattern, mitotic activity, periductal fibrosis, and lymphocytic infiltrate in 342 women. Using majority opinion-based scores for each feature, their association with subsequent iIBC risk was assessed using Cox regression. RESULTS Interrater reliability of grade using various classifications was fair to moderate, and only substantial for grade 1 versus 2 + 3 when using GAC2 (0.78). Reliability for growth pattern (KA 0.44, GAC2 0.78), calcifications (KA 0.49, GAC2 0.70) and necrosis (KA 0.47, GAC2 0.70) was moderate using KA and substantial using GAC2; for (type of) periductal fibrosis and lymphocytic infiltrate fair to moderate estimates were found and for mitotic activity reliability was substantial using GAC2 (0.70). Only in patients treated with BCS-RT, high mitotic activity was associated with a higher iIBC risk in univariable analysis (Hazard Ratio (HR) 2.53, 95% Confidence Interval (95% CI) 1.05-6.11); grade 3 versus 1 + 2 (HR 2.64, 95% CI 1.35-5.14) and a cribriform/solid versus flat epithelial atypia/clinging/(micro)papillary growth pattern (HR 3.70, 95% CI 1.34-10.23) were independently associated with a higher iIBC risk. CONCLUSIONS Using majority opinion-based scores, DCIS grade, growth pattern, and mitotic activity are associated with iIBC risk in patients treated with BCS-RT, but interrater variability is substantial. Semi-quantitative grading, incorporating and separately evaluating nuclear pleomorphism, growth pattern, and mitotic activity, may improve the reliability and prognostic value of these features

Prognostic Value of Residual Disease after Neoadjuvant Therapy in HER2-Positive Breast Cancer Evaluated by Residual Cancer Burden, Neoadjuvant Response Index, and Neo-Bioscore

Abstract Purpose: In breast cancer, pathologic complete response (pCR) to neoadjuvant systemic therapy (NST) is associated with favorable long-term outcome. Trastuzumab emtansine as additional adjuvant therapy improves recurrence-free survival of patients with HER2-positive breast cancer without pCR, but it is uncertain whether all patients without pCR need additional therapy. We evaluated the prognostic value of residual disease after trastuzumab-based NST in patients with HER2-positive breast cancer using Residual Cancer Burden (RCB), Neoadjuvant Response Index (NRI), and Neo-Bioscore. Experimental Design: We included patients with stage II or III HER2-positive breast cancer treated with trastuzumab-based NST and surgery at The Netherlands Cancer Institute between 2004 and 2016. RCB, NRI, and Neo-Bioscore were determined. Primary endpoint was 5-year recurrence-free interval (RFI). A 3% difference compared with the pCR group was considered acceptable as noninferiority margin on the 5-year RFI estimate, based on a proportional hazards model, and its lower 95% confidence boundary. Results: A total of 283 women were included. Median follow-up was 67 months (interquartile range 44–100). A total of 157 patients (56%) with pCR (breast and axilla) had a 5-year RFI of 92% (95% CI, 88–97); patients without pCR had a 5-year RFI of 80% (95% CI, 72–88). Patients with an RCB = 1 (N = 40, 15%), an NRI score between 0.75 and 0.99 (N = 30, 11%), or a Neo-Bioscore of 0 to 1 (without pCR; N = 28, 11%) have a 5-year RFI that falls within a predefined noninferiority margin of 3% compared with patients with pCR. Conclusions: The RCB, NRI, and Neo-Bioscore can identify patients with HER2-positive breast cancer with minimal residual disease (i.e., RCB = 1, NRI ≥ 0.75, or Neo-Bioscore = 0–1) after NST who have similar 5-year RFI compared with patients with pCR. </jats:sec