Breast
Therapy
Immunotherapy
Editorial Board Member: Julie M. Jorns, M.D.
Deputy Editor-in-Chief: Gary Tozbikian, M.D.
Last author update: 25 November 2024
Last staff update: 25 November 2024
Copyright: 2024, PathologyOutlines.com, Inc.
PubMed Search: Breast cancer immunotherapy
Table of Contents
Definition / general | Essential features | Terminology | Pathophysiology | Diagrams / tables | Clinical features | Prognostic factors | Case reports | Microscopic (histologic) description | Microscopic (histologic) images | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Yang E, Wen HY. Immunotherapy. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/breastimmunotherapy.html. Accessed December 26th, 2024.
Definition / general
- Immunotherapy is the treatment that harnesses the body’s immune system to fight disease, particularly cancer
- There are several types of immunotherapy, such as immune checkpoint inhibitor (ICI)
- An example of ICI is pembrolizumab, which has been FDA approved for triple negative breast cancer (TNBC)
Essential features
- Immune checkpoint inhibitors (ICI) include
- PD-1 (programmed cell death-1) inhibitor (e.g., pembrolizumab)
- Application: adjuvant therapy for PDL1 positive locally advanced or metastatic TNBC
- Companion diagnostic: PDL1 IHC 22C3 pharmDx (combined positive score [CPS] ≥ 10)
- Neoadjuvant therapy for high risk, early stage TNBC
- Application: adjuvant therapy for PDL1 positive locally advanced or metastatic TNBC
- PDL1 (programmed death ligand 1) inhibitor (e.g., atezolizumab)
- Application (FDA approval withdrawn): adjuvant therapy for PDL1 positive locally advanced or metastatic TNBC
- Companion diagnostic: VENTANA PDL1 (SP142) Assay (≥ 1% IC)
- Application (FDA approval withdrawn): adjuvant therapy for PDL1 positive locally advanced or metastatic TNBC
- PD-1 (programmed cell death-1) inhibitor (e.g., pembrolizumab)
Terminology
- Immune checkpoint inhibitors (ICI)
- Programmed death ligand 1 (PDL1)
- PD-1 inhibitor (e.g., pembrolizumab)
- PDL1 inhibitor (e.g., atezolizumab, durvalumab)
Pathophysiology
- Mechanism of action for immune checkpoint inhibitors (ICI), such as PD-1 inhibitor (e.g., pembrolizumab) and PDL1 inhibitor (e.g., atezolizumab) (Cancer Cell 2015;27:450)
- Binding of PDL1 to PD-1 inhibits T cell activity, known as immune checkpoint regulation, which prevents excessive immune activities and protects normal cells
- PDL1 is expressed in various cancer cells, allowing cancer cells to evade immune surveillance
- ICI blocks the interaction between PDL1 and PD-1, therefore enhances antitumor immune response
- PDL2 is an alternative ligand and may have a complementary role to PDL1 (J Pers Med 2024;14:478)
Diagrams / tables
Images hosted on other servers:
Landscape of anti-PD-1 and anti-PDL1 trials
Guidelines for TILs assessment
Clinical features
- The FDA approved application of ICIs for breast cancer, mainly for TNBC
- Pembrolizumab
- Mechanism: PD-1 inhibitor
- Application: pembrolizumab in adjuvant systemic therapy for PDL1 positive locally advanced or metastatic TNBC
- Landmark clinical trial: KEYNOTE-355 (Lancet 2020;396:1817)
- Companion diagnostic assay: PDL1 IHC 22C3 pharmDx
- PDL1 positive definition: CPS ≥ 10
- CPS: number of PDL1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100
- PDL1 positive definition: CPS ≥ 10
- Pembrolizumab in neoadjuvant setting for high risk, early stage TNBC regardless of PDL1 expression
- Landmark clinical trial: KEYNOTE-522 (N Engl J Med 2022;386:556)
- Other biomarkers
- Tumor mutational burden (TMB) high (≥ 10 mutations/megabase) (Clin Cancer Res 2021;27:4685)
- The FDA approved pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden high (TMB H) (≥ 10 mutations/megabase [mut/Mb]) solid tumors, as determined by an FDA approved test
- Clinical trial: KEYNOTE-158 (J Clin Oncol 2020;38:1)
- MSI H (Clin Cancer Res 2019;25:3753)
- The FDA approved pembrolizumab for select patients with MSI H or dMMR solid tumors
- Clinical trials: KN-012, 016, 028, 158 and 164 (Science 2017;357:409)
- The FDA approved pembrolizumab for select patients with MSI H or dMMR solid tumors
- The FDA approved pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden high (TMB H) (≥ 10 mutations/megabase [mut/Mb]) solid tumors, as determined by an FDA approved test
- Tumor mutational burden (TMB) high (≥ 10 mutations/megabase) (Clin Cancer Res 2021;27:4685)
- Atezolizumab
- Mechanism: PDL1 inhibitor
- Application: the FDA approved atezolizumab as adjuvant systemic therapy for PDL1 positive locally advanced or metastatic TNBC
- Landmark clinical trial: IMpassion130 (N Engl J Med 2018;379:2108)
- Companion diagnostic assay: VENTANA PDL1 (SP142) Assay
- PDL1 positivity definition: ≥ 1% IC
- % IC: proportion of tumor area occupied by PDL1 expressing tumor infiltrating immune cells of any intensity
- PDL1 positivity definition: ≥ 1% IC
- The application was withdrawn based on IMpassion131 (Ann Oncol 2021;32:983, Ann Oncol 2021;32:994)
- Pembrolizumab
- Ongoing trials exploring additional applications
- Pembrolizumab combined with poly ADP ribose polymerase (PARP) inhibitor (JAMA Oncol 2019;5:1132)
- Durvalumab (PDL1 inhibitor) combined with stereotactic body radiation therapy (SBRT) or oleclumab (anti-CD73 mAb) (BMC Cancer 2021;21:899)
Prognostic factors
- Presence of tumor infiltrating lymphocytes (TILs) in the tumor microenvironment indicates an existing antitumor immune response and is both prognostic and predictive (Nat Rev Clin Oncol 2016;13:228)
Case reports
- 44 year old woman with PDL1 negative breast cancer and response to atezolimab (Front Oncol 2021;11:710596)
Microscopic (histologic) description
- PDL1 expression is assessed using the combined positive score (CPS), a companion diagnostic assay with PDL1 IHC 22C3 pharmDx, for identifying patients with TNBC for treatment with pembrolizumab
- CPS = # PDL1 staining cells (tumor cells, lymphocytes, macrophages) / total # of viable tumor cells x 100 (Lancet 2020;396:1817)
- PDL1 staining should be included in the scoring (numerator) and is defined as
- Any noticeable and distinct linear membrane staining (≥ 1+) of viable tumor cells, clearly distinguishable from cytoplasmic staining
- Any membrane or cytoplasmic staining (≥ 1+) of lymphocytes and macrophages (mononuclear inflammatory cells, MICs) within tumor nests or the surrounding stroma
- The scored area should be defined to include only the tumor and associated stroma (CAP Today: PD-L1 Testing in Triple-Negative Breast Cancer - Post Hoc IMpassion130 Substudy Evaluates PD-L1 IHC Assay Performance [Accessed 21 October 2024])
- In situ components should be excluded from the CPS scoring
- Inflammatory cells associated with the in situ components should also be excluded from the numerator
- CPS score result
- CPS < 10: negative
- CPS ≥ 10: positive
- Minimum of 100 viable tumor cells must be present in the PDL1 stained slide (biopsy and resection) for the specimen to be considered adequate for evaluation
- Cytology and decalcified bone specimens are not suitable for PDL1 testing
Microscopic (histologic) images
Contributed by Hannah Y. Wen, M.D., Ph.D.
Primary triple negative breast carcinoma
Primary triple negative breast carcinoma
Metastatic triple negative breast carcinoma to brain
Board review style question #1
Which biomarker is used to select patients for adjuvant systemic therapy with pembrolizumab for a patient with metastatic triple negative breast cancer (TNBC)?
- Germline BRCA mutation carrier
- PDL1 CPS ≥ 1
- PDL1 CPS ≥ 10
- PDL1 expression in tumor infiltrating immune cells ≥ 1% of the tumor area
- Tumor mutational burden (TMB) ≥ 1
Board review style answer #1
C. PDL1 CPS ≥ 10.
Answer A is incorrect because poly ADP ribose polymerase (PARP) inhibitors are approved for germline BRCA mutation associated breast cancer (N Engl J Med 2018;379:753).
Answer B is incorrect because pembrolizumab is specifically approved for use in patients with metastatic triple negative breast cancer when their PDL1 CPS is ≥ 10, not ≥ 1 (Lancet 2020;396:1817).
Answer D is incorrect because PDL1 expression in tumor infiltrating immune cells ≥ 1% of the tumor area (% IC) is the assessment of PDL1 expression with the companion diagnostic assay (VENTANA PDL1 SP142) for atezolizumab.
Answer E is incorrect because pembrolizumab is approved for the treatment of unresectable or metastatic tumor mutational burden (TMB) high ≥ 10 solid tumors (J Clin Oncol 2020;38:1).
Comment Here
Reference: Breast - Immunotherapy
Comment Here
Reference: Breast - Immunotherapy
Board review style question #2
Which biomarker / tumor change, with the matched breast cancer type / setting, is most predictive of a favorable outcome?
- Dynamic TILs decrease in neoadjuvant therapy of early breast cancer
- Dynamic TILs increase in adjuvant therapy of metastatic triple negative breast cancer (TNBC)
- Dynamic TILs increase in neoadjuvant therapy of early breast cancer
- PDL1 CPS < 10 in adjuvant therapy of metastatic TNBC
- PDL1 CPS ≥ 10 in neoadjuvant therapy of early breast cancer
Board review style answer #2
C. Dynamic tumor infiltrating lymphocytes (TILs) increase in neoadjuvant therapy of early breast cancer. Answer E is incorrect because, contrary to the metastatic setting, PDL1 IHC expression was not predictive of pCR. Answers A and B are incorrect because instead, TIL levels and dynamic TILs increase were predictive of better pCR in neoadjuvant therapy of early breast cancer (Ann Oncol 2022;33:534). Answer D is incorrect because, in the metastatic TNBC setting, patients with PDL1 combined positive score (CPS) score ≥ 10 showed increased progression free survival (Lancet 2020;396:1817).
Comment Here
Reference: Breast - Immunotherapy
Comment Here
Reference: Breast - Immunotherapy
