Immunotheraphy for the Treatment of Breast Cancer

Publication Date: June 30, 2021
Last Updated: March 14, 2022

Immunotherapy With PD-(L)1 Inhibitors for the Treatment of Advanced/Metastatic Breast Cancer

Clinical trial enrollment remains a priority to further understand the benefit of checkpoint inhibition in metastatic breast cancer.
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All patients with unresectable locally advanced or metastatic TNBC should have tumor tissue tested for PD-L1 by an FDA-approved assay for breast cancer.
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  • All patients with locally advanced or metastatic breast cancer should undergo comprehensive genomic profiling, including testing for TMB and MSI.
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With the withdrawal of the indication for atezolizumab with nab-paclitaxel in metastatic TNBC, one companion diagnostic is approved by the FDA for PD-L1 testing in metastatic TNBC: the 22C3 assay with tumor and IC scoring by combined positive score. Benefit is seen for adding pembrolizumab to chemotherapy in patients with tumors expressing PD-L1 by CPS score ≥10.
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For patients with locally advanced/metastatic TNBC and PD-L1+ tumors by CPS score ≥10 using the 22C3 assay, pembrolizumab plus nab-paclitaxel, paclitaxel, or carboplatin and gemcitabine is recommended as one immunotherapy option for first-line treatment (LE:2), based on clinically meaningful PFS improvement in KEYNOTE-355.
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For patients with locally advanced/metastatic TNBC, pembrolizumab should only be added to chemotherapy (nab-paclitaxel, paclitaxel or carboplatin/ gemcitabine combination) if tumors express PD-L1 with CPS ≥10 by the 22C3 assay (until PD-L1 assays are harmonized).
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For patients with locally advanced/metastatic TNBC and PD-L1+ tumors being treated with atezolizumab, nab-paclitaxel is the only chemotherapy backbone that has demonstrated activity in randomized clinical trials.
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The indication for atezolizumab in this setting was voluntarily withdrawn in 2021.
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Patients deriving clinical benefit from atezolizumab-based treatment in the absence of clinically significant toxicity or disease progression should continue on atezolizumab plus nab-paclitaxel rather than change therapy. ()
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All patients who are candidates for immunotherapy treatment for metastatic TNBC should have tumor tissue tested for PD-L1 at least once, irrespective of line of therapy or prior immunotherapy in the adjuvant or neoadjuvant setting.
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Emerging Data on Immunotherapy With PD-(L)1 Inhibitors for Early-Stage/Locally Advanced Breast Cancer

For all patients with stage II and III TNBC, clinical trial enrollment should be considered if available.
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For patients with stage II and III TNBC, improved pCR rates with either neoadjuvant pembrolizumab or atezolizumab have been observed, regardless of PD-L1 status.
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For patients with high-risk early-stage TNBC, pembrolizumab in combination with chemotherapy as neoadjuvant treatment and then continued as a single agent as adjuvant treatment after surgery is a standard of care based on statistically significant and clinically meaningful improvement in EFS in KEYNOTE-522. Overall survival (OS) data is still maturing.
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For patients with stage II and III TNBC and no available trial, the addition of atezolizumab to standard neoadjuvant chemotherapy may be considered, although not FDA-approved at the time of publication and the IMpassion031 trial was not powered to assess EFS. (2)
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Based on accumulated data to date, immunotherapy regimens for stage II and III TNBC should at least include an anthracycline and a taxane with or without carboplatin.
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For patients with stage II and III TNBC in KEYNOTE- 522, patients continued immunotherapy from the neoadjuvant setting into the adjuvant setting. The potential benefits of adjuvant immunotherapy must be weighed against the potential for toxicities with treatment.
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Diagnostics And Biomarker Testing in Patients With Advanced/Metastatic Breast Cancer

For patients with TNBC being considered for treatment with pembrolizumab in combination with chemotherapy, tumor tissue should be tested for PD-L1 by the PD-L1 22C3 pharmDx assay and scored by the CPS system, until PD-L1 assays are harmonized.
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A TNBC is PD-L1+ by 22C3, and the patient eligible for pembrolizumab, with a CPS ≥10.
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Although PD-L1 testing of primary lesions may not correlate with expression in metastatic disease, benefit was observed in IMpassion130 with any PD-L1+ result regardless of whether primary or metastatic tumor. PD-L1 testing should be performed on the metastatic tumor, if available, but testing on primary tumor is acceptable.
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When considering metastatic sites to test for PD-L1, it is preferable to prioritize extrahepatic sites or the primary tumor, if available. ()
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Stromal TIL assessment in primary lesions is prognostic in early TNBC and HER2+ breast cancer,
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but has not been validated to direct clinical decision-making for chemotherapy or immunotherapy.
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Biomarker assessment, including repeat receptor profiles (ER/PR/HER2) and PD-L1 status as well as NGS should be considered at first relapse.
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Evaluation and Management of Treatment Response
 

  • The application of formal response criteria (ie, RECIST) is not currently recommended off-study. If one of the immune response criteria is used, the standard RECIST measurements should also be used to help with validity and cross-trial comparisons.
  • When pseudoprogression is suspected and treatment beyond progression is being considered, the patient should have stable or improved clinical condition, no severe laboratory abnormalities, and be tolerating the treatment well with limited/mild side effects. Treatment beyond progression should be discontinued in cases where clinical progression occurs or if additional progression is confirmed on subsequent imaging scans.
  • For management of isolated site(s) of progression for a patient receiving immunotherapy, it is reasonable to consider local therapy for the isolated site(s) of progression as long as the patient has good performance status and is otherwise responding to the current treatment. However, there are no data that local treatment will improve clinical outcomes.

Toxicity Considerations: Patient Selection and Management

In patients with pre-existing comorbidities, active autoimmune disease requiring systemic immunosuppression (>10 mg prednisone equivalent or biologics), or those who have experienced toxicities with prior therapies, the benefits of immunotherapy must be weighed against the potential for severe AEs.
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Patients should be monitored for symptoms of immune toxicities during immunotherapy and for at least 12 months after discontinuation of treatment. Importantly, irAEs may occur after immunotherapy has been discontinued and other therapy initiated. (1)
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For patients with early stage TNBC who receive pembrolizumab, serum cortisol should be tested at baseline, prior to surgery, and as clinically indicated. ()
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For patients with breast cancer who experience irAEs during immunotherapy treatment, management should generally follow the most updated guidelines (eg, SITC, ASCO, National Comprehensive Cancer Network (NCCN)) as this field is rapidly evolving.
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For patients with breast cancer who develop thyroid disorders or adrenal insufficiency while on treatment, immunotherapy can generally be continued. (2)
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Patient Education and QOL

  • For patients receiving immunotherapy, education should be provided, including the differences between chemotherapy and immunotherapy.
  • Whenever possible, caregivers and family members should be included in these conversations.
  • Patients should be encouraged to use contraception while receiving immunotherapy, and a discussion about fertility should be initiated prior to treatment.
  • Patients and providers should be educated about potential irAEs, including the expected timing of symptom onset and management of toxicity with immunotherapies, rationale for holding doses as opposed to dose reductions, and detailed parameters for when to contact their care team.
  • For patients being treated with immunotherapy, education should include the importance of early recognition and management of irAEs, emphasizing that some of the more common toxicities have vague symptoms and therefore any change from baseline health should be reported. Additionally, patients should be encouraged to inform all their current and future healthcare providers that they have been treated with immunotherapy.

Novel Combination Strategies and Intriguing Future Directions
 

  • Given the limited activity with currently available single-agent immunotherapy, the efficacy of immunotherapeutic strategies will likely be enhanced with combination therapy adding chemotherapy, targeted therapies, radiotherapy, or other immunotherapy agents.
  • Based on current evidence, the combinations mentioned above are investigational and should only be considered in the context of a clinical trial.
  • The optimal dose of radiation (low or high) to combine with ICIs in the preoperative setting is the subject of an ongoing clinical trial (NCT04443348). Data from this trial will permit design of large, phase II trials examining radiation and immunotherapy combinations in the pre-operative setting.
  • In ongoing and planned studies involving combination approaches with immunotherapy, both short- term and long-term toxicities should be a careful consideration.
  • Companion biomarkers that predict clinical benefit and/or toxicity are essential in the development of these strategies.

Recommendation Grading

Overview

Title

Immunotheraphy for the Treatment of Breast Cancer

Authoring Organization

Publication Month/Year

June 30, 2021

Last Updated Month/Year

July 13, 2023

Supplemental Implementation Tools

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Inclusion Criteria

Female, Adult, Older adult

Health Care Settings

Ambulatory, Hospital, Outpatient

Intended Users

Physician, nurse practitioner, nurse, physician assistant

Scope

Treatment

Diseases/Conditions (MeSH)

D007167 - Immunotherapy, D000072656 - Breast Cancer Lymphedema

Keywords

breast cancer, Metastatic Breast Cancer, Clinical Practice Guideline, immunotheraphy, anti-PD-(L)1