Stromal Tumor-infiltrating Lymphocytes in NRG Oncology/NSABP B-31 Adjuvant Trial for Early-Stage HER2-Positive Breast Cancer

Kim, Rim S.; Song, Nan; Gavin, Patrick G.; Salgado, Roberto; Bandos, Hanna; Kos, Zuzana; Floris, Giuseppe; Eynden, Gert G. G. M. Van den; Badve, Sunil; Demaria, Sandra; Fehrenbacher, Louis; Mamounas, Eleftherios P.; Swain, Sandra M.; Wickerham, D. Lawrence; Costantino, Joseph P.; Paik, Soonmyung; Wolmark, Norman; Geyer, Charles E.; Lucas, Peter C.; Pogue–Geile, Katherine L.

doi:10.1093/jnci/djz032

Cited by 44 publications

(40 citation statements)

References 21 publications

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“…TILs are known to be a strong prognostic factor in HER2-positive breast cancer and reflect a general state of immune activation. The significant prognostic effect of TILs in early HER2-positive breast cancer patients treated with adjuvant therapy has been previously demonstrated by our group and others (14,24).…”

Section: Discussionsupporting

confidence: 68%

PIK3CA Mutation in the ShortHER Randomized Adjuvant Trial for Patients with Early HER2+ Breast Cancer: Association with Prognosis and Integration with PAM50 Subtype

Guarneri

Dieci

Bisagni³

et al. 2020

Clinical Cancer Research

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We explored the prognostic effect of PIK3CA mutation in HER2-positive patients enrolled in the ShortHER trial. Experimental design: The ShortHER trial randomized 1253 patients with HER2-positive breast cancer to 9-weeks or 1-year of adjuvant trastuzumab combined with chemotherapy. PIK3CA hotspot mutations in exon 9 and 20 were analysed by Pyrosequencing. Expression of 60 genes, including PAM50 genes was measured using the nCounter platform. Results: A mutation of the PIK3CA gene was detected in 21.7% of the 803 genotyped tumors. At a median follow up of 7.7 years, 5-yr disease-free survival (DFS) rates were 90.6% for PIK3CA mutated and 86.2% for PIK3CA wild-type tumors (HR 0.84, 95%CI 0.56-1.27, P=0.417). PIK3CA mutation showed a favorable prognostic impact in the PAM50 HER2-enriched subtype (n=232): 5-yr DFS 91.8% vs 76.1% (log-rank P=0.049; HR 0.46 95%CI 0.21-1.02). HER2-enriched/ PIK3CA mutated vs wild-type tumors showed numerically higher tumor infiltrating lymphocytes (TILs) and significant upregulation of immune-related genes (including CD8A, CD274, PDCD1 and MYBL2, a proliferation gene involved in immune processes). High TILs as well as the upregulation of PDCD1 and MYBL2 were associated with a significant DFS improvement within the HER2enriched subtype (HR 0.82, 95%CI 0.68-0.99, P=0.039 for 10% TILs increment; HR 0.81, 95%CI 0.65-0.99, P=0.049 for PDCD1 expression; HR 0.72, 95%CI 0.53-0.99, P=0.042 for MYBL2 expression). Conclusions: PIK3CA mutation showed no prognostic impact in the ShortHER trial. Within the HER2-enriched molecular subtype, patients with PIK3CA mutated tumors showed better DFS vs PIK3CA wild-type that may be partly explained by upregulation of immune-related genes. Research.

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Section: Discussionsupporting

confidence: 68%

PIK3CA Mutation in the ShortHER Randomized Adjuvant Trial for Patients with Early HER2+ Breast Cancer: Association with Prognosis and Integration with PAM50 Subtype

Guarneri

Dieci

Bisagni³

et al. 2020

Clinical Cancer Research

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“…2) 22 . The last ring study was performed by six TIL-WG pathologists who independently scored 100 scanned whole section (excision specimen) breast cancer cases 23 .…”

Section: Identification Of Cases Demonstrating Variability Using Ringmentioning

confidence: 99%

“…We identified 3 ring studies evaluating concordance of sTIL assessment in breast cancer performed by TIL-WG pathologists, for which we could obtain individual pathologist data and images 22,23 . The ring studies were performed on clinical trials material.…”

Section: Identification Of Cases Demonstrating Variability Using Ringmentioning

confidence: 99%

“…A subset of 28 of the original 32 pathologists participated and scored 60 different scanned breast cancer core biopsy slides 22 . Ring study 3 was performed by six TIL-WG pathologists who independently scored 100 scanned whole slide breast cancer cases 23 . In total, 220 slides were included.…”

Section: Identification Of Cases Demonstrating Variability Using Ringmentioning

confidence: 99%

“…In an effort to identify the sources of variation in assessment of sTILs, we analyzed data and images from three-ring studies performed by TIL-WG pathologists specifically evaluating concordance in sTIL evaluation in breast cancer 22,23 . Based on the findings of this analysis we designed an educational resource available via the International Immuno-Oncology Working Group website at www.tilsinbreastcancer.org/pitfalls to assist pathologists in avoiding the different types of pitfalls identified.…”

Section: Introductionmentioning

confidence: 99%

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

Kos¹,

et al. 2020

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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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The path to a better biomarker: application of a risk management framework for the implementation of PD‐L1 and TILs as immuno‐oncology biomarkers in breast cancer clinical trials and daily practice

Gonzalez-Ericsson

Stovgaard

Sua

et al. 2020

The Journal of Pathology

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168

132

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Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin-stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD-L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immuno-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a riskmanagement framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in BC.

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Stromal Tumor-infiltrating Lymphocytes in NRG Oncology/NSABP B-31 Adjuvant Trial for Early-Stage HER2-Positive Breast Cancer

Cited by 44 publications

References 21 publications

PIK3CA Mutation in the ShortHER Randomized Adjuvant Trial for Patients with Early HER2+ Breast Cancer: Association with Prognosis and Integration with PAM50 Subtype

PIK3CA Mutation in the ShortHER Randomized Adjuvant Trial for Patients with Early HER2+ Breast Cancer: Association with Prognosis and Integration with PAM50 Subtype

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

The path to a better biomarker: application of a risk management framework for the implementation of PD‐L1 and TILs as immuno‐oncology biomarkers in breast cancer clinical trials and daily practice

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