Metastatic HER2-Negative Breast Cancer – Chemo- and Targeted Therapy

Last updated January 17, 2022

Introduction

Introduction

  • The purpose of this guideline update is to gather and examine the evidence published since the 2014 guidelinea and offer a series of updated recommendations for advanced HER2-negative breast cancer, if warranted.
  • Note that while this guideline provides recommendations for chemo- and targeted therapy for patients with HER2-negative metastatic breast cancer that is either endocrine-pretreated or hormone receptor-negative, a companion guidelineb provides endocrine therapy and targeted therapy recommendations, including CDK 4/6 and PI3 kinase inhibition, for hormone receptor-positive metastatic breast cancer patients.
a Partridge AH et al. J Clin Oncol. 2014 Oct 10;32(29):3307-29b Burstein et al. J Clin Oncol. doi: 10.1200/JCO.21.01392

Treatment

Treatment

  • Patients with metastatic triple negative breast cancer with expression of programmed cell death ligand-1 (PD-L1-positive) and no existing contraindications may be offered the addition of immune checkpoint inhibitor to chemotherapy (atezolizumab plus nab-paclitaxel or pembrolizumab plus chemotherapy) as first-line therapy.
( EB , I , B , S )
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  • Patients with metastatic triple negative breast cancer without expression of programmed cell death ligand-1 (PD-L1-negative) should be offered single agent chemotherapy rather than combination chemotherapy as first-line treatment, although combination regimens may be offered for symptomatic or immediately life-threatening disease for which time may allow only one potential chance for therapy.
( EB , I , B , S )
Practical Information: Patients may be offered either platinum- or non-platinum-based regimens based on individualized patient and provider assessment of preferences, risks, and benefits.
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  • Patients with metastatic triple negative breast cancer who have received at least two prior therapies for metastatic disease should be offered treatment with sacituzumab govitecan.
( EB , H , B , S )
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  • Patients with metastatic triple negative breast cancer with germline BRCA1 or 2 mutations who have previously been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic disease setting may be offered an oral PARP inhibitor (olaparib or talazoparib) rather than chemotherapy.
( EB , I , B , S )
Practical Information: Small single-arm studies show that oral PARP inhibitor therapy demonstrates high response rates in metastatic breast cancer encoding DNA repair defects, such as germline PALB2 mutation carriers and somatic BRCA mutations. It should also be noted that the randomized PARP inhibitor trials made no direct comparison with taxanes, anthracyclines, or platinums. Comparative efficacy against these compounds is unknown.
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  • Patients with metastatic hormone receptor-positive (HR-positive) breast cancer with disease progression on a prior endocrine agent with or without targeted therapy may be offered treatment with either endocrine therapy with or without targeted therapy (refer to the companion ASCO guideline on Endocrine Therapy and Targeted Therapy for Hormone Receptor-Positive, HER2-negative Metastatic Breast Cancer [Burstein et al. J Clin Oncol. doi: 10.1200/JCO.21.01392] for details) or single-agent chemotherapy.
( EB , I , B , S )
Practical Information: Treatment choice should be based on individualized patient and provider assessment of preferences, risks, and benefits.
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  • Patients with metastatic HR-positive but HER2-negative breast cancer with germline BRCA1 or 2 mutations who are no longer benefiting from endocrine therapy may be offered an oral PARP inhibitor in the first- through to third-line setting rather than chemotherapy. 
( EB , I , B , S )
Practical Information: Small single-arm studies show that oral PARP inhibitor therapy demonstrates high response rates in metastatic breast cancer encoding DNA repair defects, such as germline PALB2 mutation carriers and somatic BRCA mutations. It should also be noted that the randomized PARP inhibitor trials made no direct comparison with taxanes, anthracyclines, or platinums. Comparative efficacy against these compounds is unknown.
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  • Patients with HR-positive HER2-negative metastatic breast cancer no longer benefiting from endocrine therapy should be offered single agent chemotherapy rather than combination therapy, although combination regimens may be offered for symptomatic or immediately life-threatening disease for which time may allow only one potential chance for therapy. 
( EB , I , B , S )
Practical Information: Choice of chemotherapy agent should be based on individualized patient and provider assessment of preferences, risks, and benefits.
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  • No recommendation regarding at which point a patient’s care should be transitioned to hospice or best supportive care only is possible at this time.
( CB , , U, S )
Practical Information: Given the heterogeneity of breast cancer and the treatment goals of patients with breast cancer, it is not possible to identify a universal optimal time to transition to hospice or best supportive care. When to transition is a decision that should be shared between the patient and clinician in the context of an ongoing conversation regarding goals of care. The conversation about integration of supportive care and eventual consideration of hospice care should start early in the management of metastatic breast cancer.
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Table 1. Targeted Therapies for Metastatic (or locally advanced) Breast Cancer

Company
Product
Generic Name
Type Indications Dose
Merck
Keytruda
pembrolizumab
Immune Checkpoint Inhibitor Triple-negative breast cancer expressing PD-L1 200 mg every 3 weeks or 400 mg every 6 weeks with chemotherapy
Gilead
Trodelvy
sacituzumab govitecan
Trop-2-directed antibody and topoisomerase inhibitor conjugate 3rd line for triple-negative breast cancer 10 mg/kg IV once weekly on Days 1 and 8 of continuous 21-day treatment
AstraZeneca / Merck
Lynparza
olaparib
PARP Inhibitor 2nd line for HER2-negative metastatic breast cancer 300 mg taken orally twice daily
Pfizer
Talzenna
talazoparib
PARP Inhibitor Deleterious or suspected deleterious germline BRCA-mutated ( gBRCAm) HER2-negative breast cancer 1 mg taken orally once daily
Eisai
Halaven
eribulin mesylate
Microtubule inhibitor for single agent chemotherapy 3rd line for metastatic breast cancer 1.4 mg/m2 IV over 2–5 minutes on Days 1 and 8 of a 21 day cycle
R-Pharm US
Ixempra
ixabepilone
Microtubule inhibitor for single agent chemotherapy or with capecitabine 2nd line for the treatment of metastatic or locally advanced breast cancer 40 mg/m2 IV over 3 hours every 3 weeks

Figure 1. Management of Metastatic HR-positive Breast Cancer


Figure 2. Management of Metastatic Triple Negative Breast Cancer


Recommendation Grading

Source Citation

Moy B, Rumble RB, Come SE, Davidson NE, Di Leo A, Gralow JR, Hortobagyi GN, Yee D, Smith IE, Chavez-MacGregor M, Nanda R, McArthur HL, Spring L, Reeder-Hayes KE, Ruddy KJ, Unger PS, Vinayak S, Irvin WJ Jr, Armaghani A, Danso MA, Dickson N, Turner SS, Perkins CL, Carey LA. Chemotherapy and Targeted Therapy for Patients With Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Update. J Clin Oncol. 2021 Dec 10;39(35):3938-3958. doi: 10.1200/JCO.21.01374. Epub 2021 Jul 29. PMID: 34324366.

Disclaimer

This pocket guide attempts to define principles of practice that should produce high-quality patient care. It is applicable to specialists, primary care, and providers at all levels. This pocket guide should not be considered exclusive of other methods of care reasonably directed at obtaining the same results. The ultimate judgment concerning the propriety of any course of conduct must be made by the clinician after consideration of each individual patient situation. Neither IGC, the medical associations, nor the authors endorse any product or service associated with the distributor of this clinical reference tool.