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 This is an original JCO publication from 2014. Please visit the JCO website to access the full article.


Systemic Therapy for Patients With Advanced Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline


 

 Authors

Sharon H. Giordano, Sarah Temin, Jeffrey J. Kirshner, Sarat Chandarlapaty, Jennie R. Crews, Nancy E. Davidson, Francisco J. Esteva, Ana M. Gonzalez-Angulo, Ian Krop, Jennifer Levinson, Nancy U. Lin, Shanu Modi, Debra A. Patt, Edith A. Perez, Jane Perlmutter, Naren Ramakrishna, and Eric P. Winer

 

 

THE BOTTOM LINE

What is the optimal medical therapy for advanced human epidermal growth factor receptor 2 (HER2) –positive breast cancer, specifically HER2-targeted therapy, either alone or in combination with chemotherapy and/or endocrine therapy?

Target Population

  • Individuals with advanced HER2-positive breast cancer

Target Audience

  • Medical oncologists, radiation oncologists, surgeons, oncology nurses, and patients/caregivers

Recommendations

  • Clinicians should recommend HER2-targeted therapy– based combinations for first-line treatment, except for highly selected patients with estrogen receptor (ER) –positive or progesterone receptor (PgR) –positive and HER2-positive disease, for whom clinicians may use endocrine therapy alone. Type: evidence based. Evidence quality: high. Strength of recommendation: strong.
  • If a patient’s HER2-positive advanced breast cancer has progressed during or after first-line HER2-targeted therapy, clinicians should recommend second-line HER2-targeted therapy– based treatment. Type: evidence based. Evidence quality: high. Strength of recommendation: strong.
  • If a patient’s HER2-positive advanced breast cancer has progressed during or after second-line or greater HER2-targeted treatment, clinicians should recommend third-line or greater HER2-targeted therapy– based treatment. Type: evidence based. Evidence quality: intermediate. Strength of recommendation: moderate.
  • Clinicians should recommend the combination of trastuzumab, pertuzumab, and a taxane for first-line treatment, unless the patient has a contraindication to taxanes. Type: evidence based. Evidence quality: high. Strength of recommendation: strong.
  • If a patient’s HER2-positive advanced breast cancer has progressed during or after first-line HER2-targeted therapy, clinicians should recommend trastuzumab emtansine (T-DM1) as second-line treatment. Type: evidence based. Evidence quality: high. Strength of recommendation: strong.
  • If a patient’s HER2-positive advanced breast cancer has progressed during or after second-line or greater HER2-targeted therapy, but she has not received T-DM1, clinicians should offer T-DM1. Type: evidence based. Evidence quality: high. Strength of recommendation: strong.
  • If a patient’s HER2-positive advanced breast cancer has progressed during or after second-line or greater HER2-targeted treatment, but she has not received pertuzumab, clinicians may offer pertuzumab. Type: informal consensus. Evidence quality: insufficient. Strength of recommendation: weak.
  • If a patient’s HER2-positive advanced breast cancer has progressed during or after second-line or greater HER2-targeted treatment and she has already received pertuzumab and T-DM1, clinicians should recommend third-line or greater HER2-targeted therapy– based treatment. Options include lapatinib plus capecitabine, as well as other combinations of chemotherapy, and trastuzumab, lapatinib and trastuzumab, or hormonal therapy (in patients with ER-positive and/or PgR-positive disease). There is insufficient evidence to recommend one regimen over another. Type: informal consensus. Evidence quality: insufficient. Strength of recommendation: weak.
  • If a patient is receiving HER2-targeted therapy and chemotherapy combinations, the chemotherapy should continue for approximately 4 to 6 months (or longer) and/or to the time of maximal response, depending on toxicity and in the absence of progression. When chemotherapy is stopped, clinicians should continue the HER2-targeted therapy; no further change in the regimen is needed until the time of progression or unacceptable toxicities. Type: evidence based. Evidence quality: intermediate. Strength of recommendation: moderate.
  • If a patient finished trastuzumab-based adjuvant treatment 12 months before recurrence, clinicians should follow the second-line HER2-targeted therapy– based treatment recommendations. Type: evidence based. Evidence quality: intermediate. Strength of recommendation: moderate.
  • If a patient finished trastuzumab-based adjuvant treatment 12 months before recurrence, clinicians should follow the first-line HER2-targeted therapy– based treatment recommendations. Type: evidence based. Evidence quality: high. Strength of recommendation: strong.
  • If a patient’s cancer is hormone receptor positive and HER2 positive, clinicians may recommend either:
    • HER2-targeted therapy plus chemotherapy. Type: evidence based. Evidence quality: high. Strength of recommendation: strong.
    • Endocrine therapy plus trastuzumab or lapatinib (in selected cases). Type: evidence based. Evidence quality: high. Strength of recommendation: moderate.
    • Endocrine therapy alone (in selected cases). Type: evidence based. Evidence quality: intermediate. Strength of recommendation: weak.
  • If a patient has started with an HER2-positive targeted therapy and chemotherapy combination, clinicians may add endocrine therapy to the HER2-targeted therapy when chemotherapy ends and/or when the cancer progresses. Type: informal consensus. Evidence quality: insufficient. Strength of recommendation: weak.

  • In special circumstances, such as low disease burden, presence of comorbidities (contradictions to HER2-targeted therapy such as congestive heart failure), and/or presence of a long disease-free interval, clinicians may offer first-line endocrine therapy alone. Type: informal consensus. Evidence quality: intermediate. Strength of recommendation: weak.

  • Qualifying statement: Although clinicians may discuss using endocrine therapy with or without HER2-targeted therapy, the majority of patients will still receive chemotherapy plus HER2-targeted therapy.

  • Note: The guide for rating recommendations and evidence quality is provided in the Methodology Supplement.

 

 

SUMMARY OF RECOMMENDATIONS

Clinical Question

Recommendation

Evidence Rating

What is the optimal treatment for patients with HER2-positive advanced breast cancer?

 

For patients with HER2-positive advanced breast cancer, is HER2-targeted therapy recommended for all in the first-line setting?

Clinicians should recommend HER2-targeted therapy-based combinations for first-line treatment, except for highly selected patients with estrogen receptor-positive (ER+) or progesterone receptor-positive (PgR+) and HER2-positive disease for whom clinicians may use endocrine therapy alone.

Type: Evidence-based

Evidence Quality: High

Strength of Recommendation: Strong

What is the optimal treatment for patients with HER2-positive advanced breast cancer?

 

Is HER2-targeted therapy recommended for all in the second-line setting?

If a patient’s HER2-positive advanced breast cancer has progressed during or after first-line HER2-targeted therapy, clinicians should recommend second-line HER2-targeted therapy-based treatment. 

Type: Evidence-based

Evidence Quality: High

Strength of Recommendation: Strong

What is the optimal treatment for patients with HER2-positive advanced breast cancer?

 

Is HER2-targeted therapy recommended for all in the third-line setting and beyond?

If a patient’s HER2-positive advanced breast cancer has progressed during or after second- line or greater HER2-targeted treatment, clinicians should recommend third--line or greater-line HER2- targeted therapy-based treatment.

Type: Evidence-based

Evidence Quality: Intermediate

Strength of Recommendation: Moderate

Which HER2-targeted therapy (trastuzumab, lapatinib, pertuzumab, or TDM-1) ± chemotherapy should be offered?

 

What is the specific recommended regimen in first-line?

Clinicians should recommend the combination of trastuzumab, pertuzumab, and a taxane for first-line treatment, unless the patient has a contraindication to taxanes. 

Type: Evidence-based

Evidence Quality: High

Strength of Recommendation: Strong

Which HER2-targeted therapy (trastuzumab, lapatinib, pertuzumab, or TDM-1) ± chemotherapy should be offered?

 

What is the specific recommended regimen in second-line?

If a patient’s HER2-positive advanced breast cancer has progressed during or after first-line HER2-targeted therapy, clinicians should recommend T-DM1 as a second-line line treatment. 

Type: Evidence-based

Evidence Quality: High

Strength of Recommendation: Strong

Which HER2-targeted therapy (trastuzumab, lapatinib, pertuzumab, or TDM-1) ± chemotherapy should be offered?

 

What is the specific recommended regimen in third-line and beyond?

If a patient’s HER2-positive advanced breast cancer has progressed during or after second- line or greater HER2-targeted therapy, but she has not received TDM-1, clinicians should offer TDM-1. 

Type: Evidence-based

Evidence Quality: High

Strength of Recommendation: Strong

If a patient’s HER2-positive advanced breast cancer has progressed during or after second- line or greater HER2-targeted treatment, but she has not received pertuzumab, clinicians may offer pertuzumab. 

Type: Informal consensus

Evidence Quality: Insufficient

Strength of Recommendation: Weak

If a patient’s HER2-positive advanced breast cancer has progressed during or after second-line or greater HER2-targeted treatment and she has already received pertuzumab and TDM-1, clinicians should recommend third--line or greater HER2-targeted therapy-based treatment. Options include lapatinib and capecitabine, as well as other combinations of chemotherapy and trastuzumab, lapatinib and trastuzumab, or hormonal therapy (in patients with ER+ and/or PgR+ disease). There is insufficient evidence to recommend one regimen over another. 

Type: Informal consensus

Evidence Quality: Insufficient

Strength of Recommendation: Weak

What are the optimal timing, dose, schedule, and duration of treatment?

If a patient is receiving HER2-targeted therapy and chemotherapy combinations, the chemotherapy should continue for approximately 4-6 months (or longer) and/or to the time of maximal response, depending on toxicity and in the absence of progression.  When chemotherapy is stopped, clinicians should continue the HER2-targeted therapy; no further change in the regimen is needed until the time of progression or unacceptable toxicities. 

Type: Evidence-based

Evidence Quality: Intermediate

Strength of Recommendation: Moderate

How should any previous HER2 adjuvant therapy influence treatment for patients with a recurrence ≤ 12 months after adjuvant treatment?

 

 

If a patient finished trastuzumab-based adjuvant treatment ≤12 months prior to recurrence, clinicians should follow the second-line HER2-targeted therapy-based treatment recommendations.

Type: Evidence-based

Evidence Quality: Intermediate

Strength of Recommendation: Moderate

How should any previous HER2 adjuvant therapy influence treatment for patients with a recurrence > 12 months after adjuvant treatment?

If a patient finished trastuzumab-based adjuvant treatment >12 months prior to recurrence, clinicians should follow the first-line HER2-targeted therapy-based treatment recommendations.

Type: Evidence-based

Evidence Quality: High

Strength of Recommendation: Strong

What is the most appropriate first-line therapy for patients with HER2-positive/ ER+/PgR+- advanced breast cancer?

 

If a patient’s cancer is hormone receptor-positive and HER2-positive, clinicians may recommend either:

 

HER2-targeted therapy plus chemotherapy

Type: Evidence-based

Evidence Quality: High

Strength of Recommendation: Strong

Endocrine therapy plus trastuzumab or lapatinib (in selected cases)

Type: Evidence-based

Evidence Quality: High

Strength of Recommendation: Moderate

Endocrine therapy alone (in selected cases)

Type: Evidence-based

Evidence Quality: Intermediate

Strength of Recommendation: Weak

If a clinician plans to offer endocrine therapy at some point during a woman’s treatment, what is the appropriate sequencing?

If the patient has started with a HER2-positive targeted therapy and chemotherapy combination, clinicians may add endocrine therapy to the HER2-targeted therapy when chemotherapy ends and/or when the cancer progresses.

Type: Informal consensus

Evidence Quality: Insufficient

Strength of Recommendation: Weak

Can clinicians offer first-line endocrine therapy?  If so, should it always be in combination with HER2-targeted therapy?

In special circumstances, such as low disease burden, the presence of co-morbidities (contradictions to HER2-targeted therapy such as congestive heart failure), and/or the presence of a long disease free-interval, clinicians may offer first-line endocrine therapy alone.

Type: Informal consensus

Evidence Quality: Intermediate

Strength of Recommendation: Weak

Qualifying Statement:  Although the clinician may discuss using endocrine therapy with or without HER2 -targeted, the majority of patients will still receive chemotherapy plus HER2-targeted therapy

 

 

 

ASCO Guideline Disclaimer: The clinical practice guidelines and other guidance published herein are provided by the American Society of Clinical Oncology, Inc. ("ASCO") to assist practitioners in clinical decision making. The information therein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified therein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Further, the information is not intended to substitute for the independent professional judgment of the treating physician, as the information does not account for individual variation among patients. Recommendations reflect high, moderate or low confidence that the recommendation reflects the net effect of a given course of action. The use of words like "must," "must not," "should," and "should not" indicate that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating physician in the context of treating the individual patient. Use of the information is voluntary. ASCO provides this information on an "as is" basis, and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions.


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