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American Society of Clinical OncologyMedical Oncology2022advanced

Management of Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases

Published by American Society of Clinical Oncology (ASCO) · Cochrane Risk of Bias tool, GRADE, and ASCO method

27Recommendations
34References
10Tables
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Summary

AI-generated

Brain metastases are common in patients with advanced HER2-positive breast cancer, with up to half of patients experiencing brain relapse over time. Improved systemic therapies for extracranial disease have extended survival, creating a need to optimize initial brain metastasis treatments and strategies for subsequent intracranial progression.

HER2-positive breast cancerbrain metastasesASCOmedical oncologytucatinibcapecitabinetrastuzumabstereotactic radiosurgery

Key Takeaways

  • 1
    For patients with a favorable prognosis for survival and a single brain metastasis, treatment options include surgery with postoperative radiation, stereotactic radiosurgery (SRS) alone, whole-brain radiotherapy (WBRT) plus memantine (WB-M) and hippocampal avoidance (HA).
  • 2
    For patients with a favorable prognosis for survival and limited (two to four) metastases, treatment options include resection for large symptomatic lesion(s) plus postoperative radiotherapy, SRS for additional smaller lesions, or HSRT/WB-M.
  • 3
    For patients with diffuse disease and/or extensive metastases and a more favorable prognosis, SRS or WB-M and HA may be offered.
  • 4
    The HER2CLIMB regimen of tucatinib plus capecitabine plus trastuzumab may be offered to patients with HER2-positive metastatic breast cancer who have brain metastases without symptomatic mass effect.
  • 5
    For patients whose systemic disease is progressive at the time of brain metastasis diagnosis, clinicians should offer HER2-targeted therapy according to algorithms for metastatic breast cancer.

What's New in This Version

Updates include a new option to defer local therapy for a subset of the target population with asymptomatic brain metastases (utilizing the HER2CLIMB regimen) and changing the recommendation on screening to note insufficient data to recommend for or against routine surveillance with brain MRI.

Key Recommendations

Overarching Clinical Question

  • 1.0

    Multidisciplinary collaboration to formulate treatment and care plans and disease management for patients with HER2-positive metastatic breast cancer should be the standard of care.

    StrongEvidence: IntermediateEvidence based, benefits outweigh harms

Clinical Question 1

  • 2.1

    If a patient has a favorable prognosis for survival and a single brain metastasis, the patient should be evaluated by an experienced neurosurgeon for discussion of the option of surgical resection, particularly if the metastasis is > 3-4 cm and/or if there is evidence of symptomatic mass effect.

    StrongEvidence: IntermediateFormal and informal consensus
  • 2.2

    If a patient has a favorable prognosis and a single brain metastasis < 3-4 cm without symptomatic mass effect, clinicians may offer either SRS or surgical resection, depending on the location and surgical accessibility of the tumor, need for tissue diagnosis, and other considerations, such as medical risk factors for surgery and patient preference.

    WeakEvidence: IntermediateFormal consensus
  • 2.3

    If a patient has a favorable prognosis and a single brain metastasis < 2 cm without symptomatic mass effect and who has an option to proceed with HER2-directed therapy with known CNS activity, then clinicians and patients may discuss options including SRS or deferring local therapy with a MDT.

    ModerateEvidence: LowInformal consensus
  • 2.4

    For most patients with brain metastases who undergo surgical resection, clinicians should recommend postoperative radiotherapy (includes SRS, hypofractionated stereotactic radiotherapy [HSRT], and for large or multiple resection beds possibility of WB-M + HA) to the resection bed to reduce the risk of local recurrence.

    WeakEvidence: IntermediateFormal and informal consensus
  • 2.5

    If a patient has a favorable prognosis and a single brain metastasis > 3-4 cm, which clinicians and a MDT deem unresectable and unsuitable for SRS, clinicians may discuss the options of HSRT or WB-M+HA. MDTs should consult with patients in this situation.

    WeakEvidence: LowFormal and informal consensus
  • 2.6

    After treatment, serial imaging every 2-4 months may be used to monitor for local and distant brain failure (also known as local recurrence or new brain disease).

    WeakEvidence: LowFormal consensus
  • 3.0

    If a patient has a favorable prognosis and presents with multiple, but limited, metastases (defined as two-four lesions), treatment options depend on the size, resectability, and mass effect of the lesions.

  • 3.1

    In a patient who presents with limited metastases (defined as two-four lesions) suitable for SRS, clinicians may discuss SRS without WB-M + HA.

    WeakEvidence: IntermediateFormal consensus
  • 3.2

    In a patient with symptomatic lesions that are unresectable and unsuitable for SRS HSRT, clinicians may recommend WBRT plus memantine and, if feasible, hippocampal avoidance and may discuss SRS after WB-M + HA.

    WeakEvidence: LowFormal and informal consensus
  • 3.3

    For patients with limited metastases < 2 cm and not associated with symptomatic mass effect, and who have an option to proceed with HER2-directed therapy with known CNS activity, then clinicians and patients may discuss deferring local therapy with a MDT.

    ModerateEvidence: LowInformal consensus
  • 3.4

    In a patient who has a large (> 3-4 cm) lesion associated with symptomatic mass effect, clinicians may discuss surgical resection of the larger lesion, if the lesion is deemed resectable. The remaining lesions and resection bed may be treated with SRS, or HSRT with or without WB-M + HA. Clinicians should also provide symptom management.

    WeakEvidence: IntermediateFormal consensus
  • 5.0

    If a patient has brain metastases and a poor prognosis, clinicians should discuss the options of best supportive care and/or palliative care, which may or may not include radiation therapy, on a case-by-case basis.

    WeakEvidence: LowFormal consensus
  • 5.1

    For a patient with symptomatic brain metastases and poor prognosis, WB-M+HA may be offered if there is a reasonable expectation of symptomatic improvement that outweighs the acute and subacute treatment-related toxicities, including fatigue and decline in neurocognitive function.

    WeakEvidence: LowFormal consensus
  • 6.0

    If a patient has intracranial metastases that progressed despite initial therapy, treatment options will depend on the patient’s prior therapies, burden of disease, performance status, and overall prognosis.

  • 6.1

    For a patient with a favorable prognosis and limited recurrence after treatment with WBRT, clinicians may discuss SRS, surgery, systemic therapy, and/or additional palliative options. For a patient with a favorable prognosis and limited recurrence after treatment with SRS, clinicians may discuss repeat SRS, surgery, WB-M+HA, systemic therapy, and/or additional palliative options.

    ModerateEvidence: LowFormal and informal consensus
  • 6.2

    If a patient has diffuse recurrence after treatment with WBRT, clinicians may discuss palliative options such as systemic therapy (preferred) or repeat reduced-dose WBRT plus memantine and/or other palliative care options.

    WeakEvidence: LowFormal and informal consensus
  • 6.3

    If a patient has diffuse recurrence after treatment with SRS, clinicians may discuss palliative options such as WB-M + HA or systemic therapy, and/or other palliative care options.

    ModerateEvidence: LowFormal consensus

Clinical Question 1 - Diffuse Disease

  • 4.1

    If a patient has symptomatic brain leptomeningeal metastases, clinicians may recommend WBRT plus memantine. The management of leptomeningeal metastases is complex, and recommendations regarding intrathecal therapy and/or systemic therapy for leptomeningeal metastases are outside the scope of this practice guideline.

    ModerateEvidence: LowFormal consensus
  • 4.2.1

    If a patient has a more favorable prognosis and presents with many diffuse and/or extensive brain metastases (≥ five metastases) without leptomeningeal disease, clinicians may recommend SRS or WB-M + HA. For patients with metastases < 2 cm and not associated with symptomatic mass effect, and who have an option to proceed with HER2-directed therapy with known CNS activity, then clinicians and patients may discuss deferring local therapy with a MDT.

    ModerateEvidence: LowFormal and informal consensus
  • 4.2.2

    Patients with favorable prognoses are those with good performance status and effective systemic therapy options. The criteria may include KPS > 70, controlled extracranial disease, and/or whether good additional systemic therapy options for extracranial disease are available.

    WeakEvidence: LowFormal consensus

Clinical Question 2.1

  • 7.1

    The combination of tucatinib, and capecitabine and trastuzumab may be offered to patients with HER2-positive metastatic breast cancer who have brain metastases without symptomatic mass effect and whose disease has progressed on at least one previous HER2-directed therapy for metastatic disease. If these agents are used, local therapy may be delayed until there is evidence of intracranial progression.

    WeakEvidence: LowEvidence based

Clinical Question 2.2

  • 8.1

    For a patient who receives a standard surgical or radiotherapy-based approach to treat brain metastases and is receiving anti-HER2–based therapy and whose systemic disease is not progressive at the time of brain metastasis diagnosis, clinicians should not switch systemic therapy.

    ModerateEvidence: LowFormal consensus
  • 8.2

    For a patient who receives a standard surgical and/or radiotherapy-based approach to treatment of brain metastases and whose systemic disease is progressive at the time of brain metastasis diagnosis, clinicians should offer HER2-targeted therapy according to the algorithms for treatment of HER2-positive metastatic breast cancer.

    ModerateEvidence: IntermediateFormal consensus

Clinical Question 2

  • 9.1

    If a patient develops intracranial disease progression after WBRT or SRS (including when a patient is not a candidate for reirradiation), clinicians may discuss offering systemic therapy using a regimen with some evidence of activity in the setting of CNS disease.

    ModerateEvidence: IntermediateFormal consensus

Clinical Question 3

  • 10.1

    If a patient does not have a known history or symptoms of brain metastases, there are insufficient data to recommend for or against performing routine surveillance with brain magnetic resonance imaging (MRI). Clinicians and patients may discuss options using shared decision-making processes.

    WeakEvidence: LowFormal and informal consensus
  • 10.2

    Clinicians should have a low threshold for performing diagnostic brain MRI testing in the setting of any neurologic symptoms suggestive of brain involvement, such as new-onset headaches, unexplained nausea or vomiting, or change in motor or sensory function.

    StrongEvidence: LowFormal consensus

Scope & Objectives

Clinical Topic

Breast Cancer and Brain Metastases

Objectives

To provide updated evidence- and consensus-based guideline recommendations to practicing oncologists and others on the management of brain metastases for patients with human epidermal growth factor receptor 2 (HER2)–positive advanced breast cancer up to 2021.

Target Patient Population

Individuals with advanced human epidermal growth factor receptor (HER2)–positive breast cancer and brain metastases.

Target Providers

Medical oncologistsradiation oncologistsneurosurgeonsoncology nurses

Patient Criteria & Setting

Therapeutic Area

Oncology

Guideline Scope

TreatmentManagementScreening

Inclusion Criteria

  • HER2-positive advanced breast cancer and central nervous system metastases
  • Fully published English-language reports of phase II or III randomized clinical trials, rigorously conducted systematic reviews, or meta-analyses
  • Trials comparing a targeted agent (± chemotherapy and ± endocrine therapy) with another treatment regimen, placebo, or observation

Exclusion Criteria

  • meeting abstracts
  • editorials, commentaries, letters, news articles, case reports, and narrative reviews
  • published in a non-English language

Evidence Grading

System: Cochrane Risk of Bias tool, GRADE, and ASCO method

Evidence Levels

LowLow confidence that the available evidence reflects the true magnitude and direction of the net effect, or our confidence in the effect estimate is limited (GRADE/ASCO).
HighHigh confidence that the available evidence reflects the true magnitude and direction of the net effect (ASCO), or we are very confident that the true effect lies close to that of the estimate of the effect (GRADE).
Very lowWe have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect (GRADE).
InsufficientEvidence is insufficient to discern the true magnitude and direction of the net effect (ASCO).
IntermediateIntermediate confidence that the available evidence reflects the true magnitude and direction of the net effect. Further research is unlikely to alter the direction, but might alter magnitude (ASCO).

Recommendation Strength

WeakThere is some confidence that the recommendation offers the best current guidance for practice, or the desirable effects probably outweigh the undesirable effects, but appreciable uncertainty exists.
StrongThere is high confidence that the recommendation reflects best practice, or the desirable effects of an intervention outweigh its undesirable effects.
ModerateThere is moderate confidence that the recommendation reflects best practice.

Safety & Contraindications

Monitoring Guidance

After treatment, serial imaging every 2-4 months may be used to monitor for local recurrence or new brain disease.

Authors & Contributors

Naren RamakrishnaMDPhD; Carey K. AndersMD; Nancy U. LinMD; Aki MorikawaMDPhD; Sarah TeminMSPH; Sarat ChandarlapatyMDPhD; Jennie R. CrewsMD; Nancy E. DavidsonMD; Maria Alice B. FranzoiMD; Jeffrey J. KirshnerMD; Ian E. KropMDPhD; Debra A. PattMDMPHMBA; Jane PerlmutterPhD; and Sharon H. GiordanoMDMPH

Guideline Features

Flowcharts includedBased on systematic reviewMultidisciplinaryPatient involvement

Learning Context

Difficulty

advanced

Learning Paths

HER2-positive breast cancerBrain metastasesStereotactic radiosurgery (SRS)Whole-brain radiotherapy (WBRT)TucatinibHER2CLIMBLocal therapySystemic therapy