New ASCO Guidelines Address HER2-Positive Breast Cancer

Laurie Barclay, MD

May 07, 2014

Most patients with advanced HER2-positive breast cancer should receive HER2-targeted drugs. But which of the several targeted agents available should be used, and in which order?

A new evidence-based guideline from the American Society of Clinical Oncology (ASCO), published online May 5 in the Journal of Clinical Oncology, addresses those issues.

The purpose of the clinical practice guideline is to provide oncologists and other clinicians with evidence-based recommendations on systemic therapy for patients with HER2-positive advanced breast cancer, write Sharon H. Giordano, from the University of Texas M.D. Anderson Cancer Center in Houston, and colleagues. They note that HER2-positive tumors account for about 15% of all breast cancer, although some estimates put that figure at around 25%.

In particular, say the authors, the rationale for the new guideline was to provide recommendations on use of the targeted agents that have been approved in recent years. After the first HER2-targeted therapy trastuzumab (Herceptin) was launched in 1998, lapatinib (Tykerb) and more recently pertuzumab (Perjeta) and ado-trastuzumab emastine, also known as TDM-1 (Kadcyla), entered the market.

The guideline is based on a systematic review of literature published from January 2009 to October 2012 that addressed overall survival, progression-free survival, and adverse events.

Among the 16 trials meeting the inclusion criteria was the CLEOPATRA trial, which showed that overall and progression-free survival improved after first-line treatment with docetaxel, trastuzumab, and pertuzumab. In another, the EMILIA trial, overall and progression-free survival improved after second-line treatment with T-DM1, and progression-free survival improved after third-line treatment with T-DM1.

Specific Recommendations for Patients With Advanced HER2-Positive Breast Cancer

Most patients should receive HER2-targeted therapy (evidence quality, high; recommendation, strong)
Patients with clinical congestive heart failure or significantly compromised left ventricular ejection fraction should be evaluated for HER2-targeted therapy on an individual basis, as should those with estrogen receptor (ER)-positive or progesterone receptor (PgR)-positive tumors (evidence quality, high; recommendation, strong)
First-line treatment should be trastuzumab, pertuzumab, and taxane, unless the patient has a contraindication to taxanes (evidence quality, high; recommendation, strong)
Patients who completed trastuzumab-based adjuvant treatment more than 12 months before recurrence should follow the recommendations for first-line HER2-targeted therapy (evidence quality, high; recommendation, strong)
Patients who completed trastuzumab-based adjuvant treatment 12 months or less before recurrence should follow the recommendations for second-line HER2-targeted therapy (evidence quality, intermediate; recommendation, moderate)
Patients who progress during or after first-line HER2-targeted treatment should receive second-line HER2-targeted treatment with T-DM1 (evidence quality, high; recommendation, strong)
Patients who progress during or after second-line or greater HER2-targeted therapy should receive third-line or greater HER2-targeted therapy (evidence quality, intermediate; recommendation, moderate)
Patients who progress during or after second-line or greater HER2-targeted therapy can be offered T-DM1 as third-line treatment if they have not previously received it (evidence quality, high; recommendation, strong)
Patients who progress during or after second-line or greater HER2-targeted therapy can be offered pertuzumab as third-line treatment if they have not previously received it (evidence quality, insufficient; recommendation, weak)
Patients who progress during or after second-line or greater HER2-targeted therapy who have already received T-DM1 and pertuzumab can be offered other HER2-targeted therapy combinations, such as 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) (evidence quality, insufficient; recommendation, weak)
Optimal duration of chemotherapy for patients receiving HER2-targeted therapy is 4 to 6 months or until maximum response, depending on toxicity and the absence of progression. When chemotherapy is stopped, HER2-targeted therapy should continue with no further changes until progression or unacceptable toxicity (evidence quality, intermediate; recommendation, moderate)
Patients with HER2-positive and ER- or PgR-positive breast cancer can receive standard first-line treatment (evidence quality, high; recommendation, strong); for select patients, endocrine therapy plus HER2-targeted therapy (evidence quality, high; recommendation, moderate) or endocrine therapy alone (evidence quality, intermediate; recommendation, weak) can be appropriate

Expert Consensus Guidelines for Patients With Brain Metastases

Accompanying consensus-based recommendations address the management of patients with advanced HER2-positive breast cancer who develop brain metastases. Because of the lack of clinical trial evidence, these recommendations are based mainly on expert consensus.

This guideline is needed, in some measure, because of the success of HER2-targeted therapy, which has improved survival for patients with early-stage and metastatic breast cancers, write Naren Ramakrishna, MD, PhD, from the University of Florida Health Cancer Center at Orlando Health, and colleagues. However, they note, HER2 positivity is a known risk factor for the development of brain metastases.

The systematic literature review did not identify sufficiently strong evidence, so the expert panel used a modified Delphi process and a formal process based on expert consensus to generate draft recommendations. The original panel and another group of experts subjected the draft recommendations to 2 rounds of formal ratings.

Final Recommendations for Patients With Advanced HER2-Positive Breast Cancer and Brain Metastases

Because patients with HER2-positive advanced breast cancer have a high incidence of brain metastases, clinicians should have a low threshold for brain MRI on the basis of symptoms or history of brain metastases, but should not routinely perform MRI to screen for brain metastases
For patients whose systemic disease is not progressive when brain metastasis is diagnosed, systemic therapy should not be switched
Patients with progressive systemic disease when brain metastasis is diagnosed should receive HER2-targeted therapy in accordance with the recommendations for HER2-positive metastatic breast cancer
Patients should receive appropriate local therapy and systemic therapy, if indicated, on the basis of prognosis, symptoms, resectability, number and size of metastases, previous treatment, and nature of metastases (diffuse vs focal)
For patients with a favorable prognosis for survival and a single brain metastasis or 2 to 4 brain metastases, appropriate local therapy includes surgery with postoperative radiation, whole-brain radiotherapy (WBRT), fractionated stereotactic radiotherapy, and/or stereotactic radiosurgery; these patients should be monitored after treatment with serial imaging every 2 to 4 months
Patients with a more favorable prognosis despite diffuse disease or extensive metastases, those with symptomatic leptomeningeal brain metastasis, and those with poor prognosis can be offered WBRT
Other management interventions can include systemic therapy, best supportive care, clinical trial enrollment, and/or palliative care

Some of the guideline authors report various financial relationships with Esteva, Genentech, Novartis, Roche, AstraZeneca, Pfizer, GlaxoSmithKline, Brainlab Ag Research Funding, Bristol-Myers Squibb, Synta Pharmaceuticals, Array Biopharma, and Geron.

J Clin Oncol. Published online May 5, 2014. Breast cancer abstract, Breast cancer and brain metastases abstract

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